DARZALEX Concentrate for solution for infusion Ref.[8950] Active ingredients: Daratumumab

DARZALEX should be administered by a healthcare professional, in an environment where resuscitation facilities are available.

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

Posology

Dosing schedule in combination with lenalidomide (4-week cycle regimen) and for monotherapy:

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 1.

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

^a First dose of the every-2-week dosing schedule is given at Week 9
^b First dose of the every-4-week dosing schedule is given at Week 25

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

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):

^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):

^a First dose of the every-2-week dosing schedule is given at Week 9
^b First dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT

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

Dosing schedule in combination with bortezomib (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 (3-week cycle dosing regimen):

^a First dose of the every-3-week dosing schedule is given at Week 10
^b First dose of the every-4-week dosing schedule is given at Week 25

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

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the 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:

^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 1,000 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 medications 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 (s)

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity (see section 4.4). For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.

Recommended concomitant medications

Pre-infusion medication

Pre-infusion medications should be administered to reduce the risk of IRRs to all patients 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-medication 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-medication.
• Antipyretics (oral paracetamol 650 to 1,000 mg)
• Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Post-infusion medication

Post-infusion medications should be administered to reduce the risk of delayed infusion-related reactions 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 medications may not be needed (see section 5.1).

Additionally, for patients with a history of chronic obstructive pulmonary disease, the use of post-infusion medications 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 medications 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 dosage 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 dosage 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 (see section 5.1).

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.

Symptoms and signs

There has been no experience of overdosage 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 effects and appropriate symptomatic treatment should be instituted immediately.

Shelf life

Unopened vials: 24 months.

After dilution: From a microbiological point of view, unless the method of opening/ dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should be no more than 24 hours at refrigerated conditions (2°C-8°C) protected from light, followed by 15 hours (including infusion time) at room temperature (15°C-25°C) and room light.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

5 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off button containing 100 mg of daratumumab. Pack size of 1 vial.

20 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off button containing 400 mg of daratumumab. Pack size of 1 vial.

DARZALEX is also supplied as an initiation pack containing 11 vials: (6 × 5 mL vials + 5 × 20 mL vials).

This medicinal product is for single-use only.

Prepare the solution for infusion using aseptic technique as follows:

• Calculate the dose (mg), total volume (mL) of DARZALEX solution required and the number of DARZALEX vials needed based on patient weight.
• Check that the DARZALEX solution is colourless to yellow. Do not use if opaque particles, discolouration or other foreign particles are present.
• Using aseptic technique, remove a volume of 0.9% Sodium Chloride from the infusion bag/container that is equal to the required volume of DARZALEX solution.
• Withdraw the necessary amount of DARZALEX solution and dilute to the appropriate volume by adding to an infusion bag/container containing 0.9% Sodium Chloride (see section 4.2). Infusion bags/containers must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.
• Gently invert the bag/container to mix the solution. Do not shake.
• Visually inspect parenteral medicinal products for particulate matter and discolouration prior to administration. The diluted solution may develop very small, translucent to white proteinaceous particles, as daratumumab is a protein. Do not use if visibly opaque particles, discolouration or foreign particles are observed.
• Since DARZALEX does not contain a preservative, diluted solutions should be administered within 15 hours (including infusion time) at room temperature (15°C-25°C) and in room light.
• If not used immediately, the diluted solution can be stored prior to administration for up to 24 hours at refrigerated conditions (2°C-8°C) and protected from light. Do not freeze.
• Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometre). Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE administration sets must be used.
• Do not infuse DARZALEX concomitantly in the same intravenous line with other agents.
• Do not store any unused portion of the infusion solution for reuse. Any unused product or waste material should be disposed of in accordance with local requirements.