BLINCYTO Powder for concentrate solution Ref.[6566] Active ingredients: Blinatumomab

Source: European Medicines Agency (EU)  Revision Year: 2019  Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands

Therapeutic indications

BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL).

BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.

BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.

Posology and method of administration

Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of haematological malignancies.

For the treatment of Philadelphia chromosome negative relapsed or refractory B-precursor ALL, hospitalisation is recommended for initiation at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.

For the treatment of Philadelphia chromosome negative MRD positive B-precursor ALL, hospitalisation is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles.

In patients with a history or presence of clinically relevant central nervous system (CNS) pathology (see section 4.4), hospitalisation is recommended at a minimum for the first 14 days of the first cycle. In the second cycle, hospitalisation is recommended at a minimum for 2 days, and clinical judgment should be based on tolerance to BLINCYTO in the first cycle. Caution should be exercised as cases of late occurrence of first neurological events have been observed.

For all subsequent cycle starts and reinitiation (e.g. if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalisation is recommended.

BLINCYTO infusion bags should be prepared to infuse over 24 hours, 48 hours, 72 hours, or 96 hours. See method of administration.

Posology

Philadelphia chromosome negative relapsed or refractory B-precursor ALL

Patients may receive 2 cycles of treatment. A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval.

Patients who have achieved complete remission (CR/CRh*) after 2 treatment cycles may receive up to 3 additional cycles of BLINCYTO consolidation treatment, based on an individual benefits-risks assessment.

Recommended daily dose is by patient weight. Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).

Premedication and additional medication recommendations

In adult patients, dexamethasone 20 mg intravenous should be administered 1 hour prior to initiation of each cycle of BLINCYTO therapy.

In paediatric patients, dexamethasone 10 mg/m² (not to exceed 20 mg) should be administered orally or intravenously 6 to 12 hours prior to the start of BLINCYTO (cycle 1, day 1). This should be followed by dexamethasone 5 mg/m² orally or intravenously within 30 minutes prior to the start of BLINCYTO (cycle 1, day 1).

Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of each treatment cycle.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.

Pre-phase treatment for patients with high tumour burden

For patients with ≥50% leukaemic blasts in bone marrow or >15,000/microlitre peripheral blood leukaemic blast counts treat with dexamethasone (not to exceed 24 mg/day).

MRD positive B-precursor ALL

When considering the use of BLINCYTO as a treatment for Philadelphia chromosome negative MRD positive B-precursor ALL, quantifiable MRD should be confirmed in a validated assay with minimum sensitivity of 10 -4 (see section 5.1). Clinical testing of MRD, regardless of the choice of technique, should be performed by a qualified laboratory familiar with the technique, following well established technical guidelines.

Patients may receive 1 cycle of induction treatment followed by up to 3 additional cycles of BLINCYTO consolidation treatment. A single cycle of treatment of BLINCYTO induction or consolidation is 28 days (4 weeks) of continuous intravenous infusion followed by a 14 day (2 week) treatment-free interval (total 42 days). The majority of patients who respond to blinatumomab achieve a response after 1 cycle (see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 1 treatment cycle should be assessed by the treating physician.

Recommended dose (for patients at least 45 kg in weight):

Treatment cycle(s)
Induction Cycle 1
Days 1-28Days 29-42
28 mcg/day14-day treatment-free interval
Consolidation Cycles 2-4
Days 1-28 Days 29-42
28 mcg/day14-day treatment-free interval

Premedication and additional medication recommendations

Prednisone 100 mg intravenously or equivalent (e.g. dexamethasone 16 mg) should be administered 1 hour prior to initiation of each cycle of BLINCYTO therapy.

Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of each treatment cycle.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.

Dose adjustments

For patients with Philadelphia chromosome negative relapsed or refractory B-precursor ALL and patients with MRD positive B-precursor ALL receiving BLINCYTO, consideration to discontinue BLINCYTO temporarily or permanently as appropriate should be made in the case of the following severe (grade 3) or life-threatening (grade 4) toxicities (see section 4.4): cytokine release syndrome, tumour lysis syndrome, neurological toxicity, elevated liver enzymes and any other clinically relevant toxicities.

If the interruption of treatment after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse event is longer than 7 days, start a new cycle. If the toxicity takes more than 14 days to resolve, discontinue BLINCYTO permanently, except if described differently in the table below.

Special populations

Elderly

No dose adjustment is necessary in elderly patients (≥65 years of age), see section 5.1. There is limited experience with BLINCYTO in patients ≥75 years of age.

Renal impairment

Based on pharmacokinetic analyses, dose adjustment is not necessary in patients with mild to moderate renal dysfunction (see section 5.2). The safety and efficacy of BLINCYTO have not been studied in patients with severe renal impairment.

Hepatic impairment

Based on pharmacokinetic analyses, no effect of baseline liver function on blinatumomab exposure is expected and adjustment of the initial dose is not necessary (see section 5.2). The safety and efficacy of BLINCYTO have not been studied in patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of BLINCYTO in children <1 year of age have not yet been established. There are no data for children <7 months of age. Currently available data in children are described in section 4.8 and 5.1.

Method of administration

Important note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, BLINCYTO should be infused through a dedicated lumen.

For instructions on the handling and preparation of the medicinal product before administration, see section 6.6.

BLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump over a period of up to 96 hours.

The BLINCYTO solution for infusion must be administered using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter.

The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO.

Infuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates:

  • Infusion rate of 10 mL/h for a duration of 24 hours
  • Infusion rate of 5 mL/h for a duration of 48 hours
  • Infusion rate of 3.3 mL/h for a duration of 72 hours
  • Infusion rate of 2.5 mL/h for a duration of 96 hours

The choice of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes. The target therapeutic dose of BLINCYTO delivered does not change.

Change of infusion bag

The infusion bag must be changed at least every 96 hours by a healthcare professional for sterility reasons.

Overdose

Overdoses have been observed including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, the infusion should be temporarily interrupted and patients should be monitored. Reinitiation of BLINCYTO at the correct therapeutic dose should be considered when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion (see section 4.2).

Shelf life

Shelf life

Unopened vials: 5 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C or 4 hours at or below 27°C.

From a microbiological point of view, unless the method of reconstituting precludes the risks of microbial contamination, the reconstituted solution should be diluted immediately. If not diluted immediately, in-use storage times and conditions are the responsibility of the user.

Diluted solution (prepared infusion bag): Chemical and physical in-use stability has been demonstrated for 10 days at 2°C-8°C or 96 hours at or below 27°C.

From a microbiological point of view, the prepared infusion bags should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Special precautions for storage

Store and transport refrigerated (2°C-8°C).

Do not freeze.

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

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

Nature and contents of container

Each BLINCYTO pack contains 1 vial of powder for concentrate for solution for infusion and 1 vial of solution (stabiliser):

  • 38.5 micrograms blinatumomab powder in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) and a flip off cap and
  • 10 mL solution in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) and a flip off cap.

Special precautions for disposal and other handling

Aseptic preparation

Aseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should be:

  • performed under aseptic conditions by trained personnel in accordance with good practice rules especially with respect to the aseptic preparation of parenteral products.
  • prepared in a laminar flow hood or biological safety cabinet using standard precautions for the safe handling of intravenous agents.

It is very important that the instructions for preparation and administration provided in this section are strictly followed to minimise medication errors (including underdose and overdose).

Special instructions to support accurate preparation

  • A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the pre-filled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution (stabiliser) for reconstitution of BLINCYTO powder for concentrate.
  • The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume to be administered to the patient (240 mL). This is to account for intravenous infusion line loss and to assure that the patient will receive the full dose of BLINCYTO.
  • When preparing an infusion bag, remove all air from infusion bag. This is particularly important when using an ambulatory infusion pump.
  • Use the specific volumes described in the reconstitution and dilution instructions below to minimise errors in calculation.

Other instructions

  • BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes.
  • Pump specifications: The infusion pump to administer BLINCYTO solution for infusion should be programmable, lockable and have an alarm. Elastomeric pumps should not be used.
  • Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation of the solution for infusion

Specific reconstitution and dilution instructions are provided for each dose and infusion time. Verify the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation section listed below. Table 7 provides instructions for patients weighing greater than or equal to 45 kg, whereas table 8 and table 9 provide instructions for patients weighing less than 45 kg. Follow the steps for reconstituting BLINCYTO and preparing the infusion bag detailed below table 9.

Table 7. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag:

Table 8. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag for 5 mcg/m²/day dose:

Table 9. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag for 15 mcg/m²/day dose:

BSA = body surface area

These supplies are also required, but not included in the package

  • Sterile single-use disposable syringes
  • 21-23 gauge needle(s) (recommended)
  • Water for injections
  • Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection;
    • To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. BLINCYTO dose calculations are based on a usual overfill volume of 265 to 275 mL sodium chloride 9 mg/mL (0.9%) solution for injection.
    • Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate (EVA) infusion bags/pump cassettes.
  • Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter.
    • Ensure that the tubing is compatible with the infusion pump.

Reconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection:

  1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection that usually contains a total volume of 265 to 275 mL.
  2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution (stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard the remaining solution (stabiliser) vial.
  3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of water for injections. Direct the water for injections toward the side of the vial during reconstitution. Gently swirl contents to avoid excess foaming. Do not shake. Do not reconstitute BLINCYTO powder for concentrate with the solution (stabiliser). The addition of water for injections to the powder for concentrate results in a total volume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL.
  4. Visually inspect the reconstituted solution for particulate matter and discolouration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has precipitated.
  5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to table 7 to table 9 for the specific volume of reconstituted BLINCYTO). Gently mix the contents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted solution.
  6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile 0.2 micron in-line filter.
  7. Remove air from the infusion bag and prime the intravenous infusion line only with the prepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) solution for injection.
  8. Store at 2°C-8°C if not used immediately.

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