Posology : מינונים

4.2        Posology and method of administration

DARZALEX 20MG/ML I.V 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 (4-week cycle regimen) and for monotherapy: The recommended dose is DARZALEX 20MG/ML I.V 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 1.

Table 1:    DARZALEX 20MG/ML I.V dosing schedule in combination with lenalidomide (4- week cycle dosing regimen) and monotherapy
Weeks                                      Schedule
Weeks 1 to 8                               weekly (total of 8 doses)
Weeks 9 to 24 a every two weeks (total of 8 doses)
Week 25 onwards until disease progressionb every four weeks a
First dose of the every-2-week dosing schedule is given at week 9 b
First dose of the every-4-week dosing schedule is given at week 25

For dose and schedule of medicinal products administered with DARZALEX 20MG/ML I.V, 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 20MG/ML I.V 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 2.

Table 2:    DARZALEX 20MG/ML I.V 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 20MG/ML I.V, 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 20MG/ML I.V 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 3.

Table 3:   DARZALEX 20MG/ML I.V 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 16 a every two weeks (total of 4 doses)
Stop for high dose chemotherapy and ASCT
Consolidation                      Weeks 1 to 8b                             every two weeks (total of 4 doses) a
First dose of the every-2-week dosing schedule is given at week 9 b
First dose of the every-2-week dosing schedule is given at week 1 upon re-initiation of treatment following ASCT 
For dose and schedule of medicinal products administered with DARZALEX 20MG/ML I.V, 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 DARZALEX 20MG/ML I.V 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in table 4.

Table 4:    DARZALEX 20MG/ML I.V dosing schedule in combination with bortezomib (3- week cycle dosing regimen)
Weeks                                      Schedule
Weeks 1 to 9                               weekly (total of 9 doses)
Weeks 10 to 24a                            every three weeks (total of 5 doses) Week 25 onwards until disease progression every four weeks b a
First dose of the every-3-week dosing schedule is given at week 10 b
First dose of the every-4-week dosing schedule is given at week 25

For dose and schedule of medicinal products administered with DARZALEX 20MG/ML I.V, see section 5.1 and the corresponding Summary of Product Characteristics.

Infusion rates
Following dilution the DARZALEX 20MG/ML I.V 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 20MG/ML I.V (16 mg/kg) administration Dilution      Initial rate         Rate incrementa            Maximum rate volume        (first hour)
Week 1 Infusion
Option 1 (Single dose infusion)
Week 1 day 1 (16 mg/kg)            1000 mL        50 mL/hour        50 mL/hour every hour           200 mL/hour Option 2 (Split dose infusion)
Week 1 day 1 (8 mg/kg)              500 mL         50 mL/hour       50 mL/hour every hour           200 mL/hour Week 1 day 2 (8 mg/kg)              500 mL         50 mL/hour       50 mL/hour every hour           200 mL/hour Week 2 (16 mg/kg)infusionb                500 mL         50 mL/hour       50 mL/hour every hour           200 mL/hour Subsequent (week 3 onwards,               500 mL        100 mL/hour       50 mL/hour every hour           200 mL/hour 16 mg/kg) infusionsc 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 20MG/ML I.V.

For IRRs of any grade/severity, immediately interrupt the DARZALEX 20MG/ML I.V infusion and manage symptoms.

Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX 20MG/ML I.V 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 20MG/ML I.V upon the third occurrence of a grade 3 or greater infusion reaction.
•     Grade 4 (life-threatening): Permanently discontinue DARZALEX 20MG/ML I.V treatment.

Missed dose
If a planned dose of DARZALEX 20MG/ML I.V 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 20MG/ML I.V 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 20MG/ML I.V, 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 20MG/ML I.V 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 20MG/ML I.V infusion. When dexamethasone is the background-regimen specific corticosteroid, the dexamethasone treatment dose will instead serve as pre-infusion medicinal product on DARZALEX 20MG/ML I.V infusion days (see section 5.1).
Dexamethasone is given intravenously prior to the first DARZALEX 20MG/ML I.V 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 20MG/ML I.V 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 20MG/ML I.V infusion. However, if a background regimen-specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX 20MG/ML I.V infusion, additional post-infusion medicinal products may not be needed (see section 5.1).

Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-infusion medicinal products including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post-infusion medicinal products may be discontinued at the discretion of the physician.

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

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

Hepatic impairment
No formal studies of daratumumab in patients with hepatic impairment have been conducted.
Based on population PK analyses, no dose adjustments are necessary for patients with hepatic impairment (see section 5.2).

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

Paediatric population
DARZALEX 20MG/ML I.V is not indicated for children under 18 years old.
The safety and efficacy of DARZALEX 20MG/ML I.V in children aged below 18 years of age have not been established.
No data are available.

Method of administration
DARZALEX 20MG/ML I.V 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.