Posology : מינונים

4.2    Posology and method of administration

DARZALEX 120MG/ML S.C. 1,800MG subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified.


DARZALEX 120MG/ML S.C. 1,800MG should be administered by a healthcare professional, and the first dose should be administered in an environment where resuscitation facilities are available.

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 120MG/ML S.C.
1,800MG 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

Dosing schedule in combination with lenalidomide (4-week cycle regimen) and for monotherapy 
The recommended dose is 1,800 mg of DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 1.

Table 1:    DARZALEX 120MG/ML S.C. 1,800MG dosing schedule in combination with lenalidomide (4-week cycle dosing regimen) and monotherapy
Weeks                                      Schedule
Weeks 1 to 8                               weekly (total of 8 doses)
Weeks 9 to 24a                             every two weeks (total of 8 doses) Week 25 onwards until disease progressionb every four weeks a
First dose of the every-2-week dosing schedule is given at week 9 b
First dose of the every-4-week dosing schedule is given at week 25

For dose and schedule of medicinal products administered with DARZALEX 120MG/ML S.C.
1,800MG 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 1,800 mg of DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 2.

Table 2:    DARZALEX 120MG/ML S.C. 1,800MG 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 54 a 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 120MG/ML S.C. 1,800MG 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 1,800 mg of DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 3.

Table 3:    DARZALEX 120MG/ML S.C. 1,800MG 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 120MG/ML S.C.
1,800MG solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Dosing schedule in combination with bortezomib (3-week cycle regimen) 
The recommended dose is 1,800 mg of DARZALEX 120MG/ML S.C. 1,800MG solution for subcutaneous injection administered over approximately 3-5 minutes according to the following dosing schedule in table 4.

Table 4:    DARZALEX 120MG/ML S.C. 1,800MG 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 24 a every three weeks (total of 5 doses)
Week 25 onwards until disease progressionb every four weeks a
First dose of the every-3-week dosing schedule is given at week 10 b
First dose of the every-4-week dosing schedule is given at week 25

For dose and schedule of medicinal products administered with DARZALEX 120MG/ML S.C.
1,800MG solution for subcutaneous injection, see section 5.1 and the corresponding Summary of Product Characteristics.

Missed dose
If a planned dose of DARZALEX 120MG/ML S.C. 1,800MG 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 120MG/ML S.C. 1,800MG 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 120MG/ML S.C. 1,800MG, see corresponding Summary of Product Characteristics.

In clinical studies, no modification to rate or dose of DARZALEX 120MG/ML S.C. 1,800MG 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 120MG/ML S.C.
1,800MG 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 120MG/ML S.C. 1,800MG 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 120MG/ML S.C. 1,800MG administration days (see section 5.1). Additional background regimen specific corticosteroids (e.g. prednisone) should not be taken on DARZALEX 120MG/ML S.C.
1,800MG administration days when patients have received dexamethasone (or equivalent) as a pre-injection medicinal product.
•     Antipyretics (paracetamol 650 to 1,000 mg).
•     Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

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 120MG/ML S.C. 1,800MG injection. However, if a background regimen specific corticosteroid (e.g. dexamethasone, prednisone) is administered the day after the DARZALEX 120MG/ML S.C. 1,800MG 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
DARZALEX 120MG/ML S.C. 1,800MG is not indicated for children and adolescents under 18 years old.
The safety and efficacy of DARZALEX 120MG/ML S.C. 1,800MG in children aged below 18 years of age have not been established.

Body weight (>120 kg)
Limited number of patients with body weight >120 kg have been studied using flat-dose (1,800 mg) DARZALEX 120MG/ML S.C. 1,800MG 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 120MG/ML S.C. 1,800MG subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. 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 120MG/ML S.C. 1,800MG 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 120MG/ML S.C. 1,800MG solution for subcutaneous injection at other sites of the body as no data are available.
Injection sites should be rotated for successive injections.

DARZALEX 120MG/ML S.C. 1,800MG 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 120MG/ML S.C. 1,800MG solution for subcutaneous injection, do not administer other medicinal products for subcutaneous use at the same site as DARZALEX 120MG/ML S.C. 1,800MG.