Posology : מינונים

4.2   Posology and method of administration
Treatment should be initiated under the direction of and supervised by physicians experienced in the treatment of hematological malignancies. Patients treated with BLINCYTO should be given the Educational Brochure for Patients and Caregivers and the Patient Card.

For the treatment of relapsed or refractory B-precursor ALL, hospitalization 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, hospitalization is recommended at a minimum for the first 3 days of the first cycle and the first 2 days of subsequent cycles.

For pediatric patients with high-risk first relapsed B-precursor ALL, hospitalization is recommended at a minimum for the first 3 days of the cycle.

In patients with a history or presence of clinically relevant central nervous system (CNS) pathology (see section 4.4), hospitalization is recommended at a minimum for the first 14 days of the first cycle.
In the second cycle, hospitalization 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 hospitalization is recommended.

Posology

Relapsed or refractory B-precursor ALL
Patients with relapsed or refractory B-precursor ALL, 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 weeks) 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 (see table 1). 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).



Table 1. BLINCYTO recommended dosage for relapsed or refractory B-precursor ALL 
Patient                      Cycle 1                              Subsequent cycles weight        Days 1-7        Days 8-28        Days 29-42       Days 1-28       Days 29-42 Greater than   9 mcg/day via    28 mcg/day       14-day           28 mcg/day      14-day or equal to    continuous       via continuous   treatment-free   via continuous treatment-free 45 kg          infusion         infusion         interval         infusion        interval
(fixed-dose)
Less than      5 mcg/m2/day     15 mcg/m2/day                     15 mcg/m2/day 45 kg          via              via continuous                    via continuous
(BSA-based     continuous       infusion                          infusion dose)          infusion         (not to exceed                    (not to exceed (not to exceed   28 mcg/day)                       28 mcg/day)
9 mcg/day)


High-risk first relapsed B-precursor ALL
Pediatric patients with high-risk first relapsed B-precursor ALL may receive 1 cycle of BLINCYTO treatment after induction and 2 blocks of consolidation chemotherapy. A single cycle of treatment is 28 days (4 weeks) of continuous infusion. See table 2 for the recommended daily dose by patient weight for pediatric patients.

Table 2. BLINCYTO recommended dosage for pediatric patients with high-risk first relapsed B-precursor ALL post-induction chemotherapy

Patient weight greater than or    Patient weight less than 45 kg
One consolidation cycle         equal to 45 kg                    (BSA-based dose) (fixed-dose)
Days 1-28                       28 mcg/day                        15 mcg/m2/day (not to exceed 28 mcg/day)

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 pediatric 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 tumor burden

For patients with ≥ 50% leukemic blasts in bone marrow or > 15,000/microliter peripheral blood leukemic 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 weeks) 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 hematological 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 1-28                                             Days 29-42
28 mcg/day                                   14-day treatment-free interval
Consolidation Cycles 2-4
Days 1-28                                             Days 29-42
28 mcg/day                                   14-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 relapsed or refractory B-precursor ALL and patients with Philadelphia chromosome negative 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, tumor lysis syndrome, neurological toxicity, elevated liver enzymes and any other clinically relevant toxicities.

If the interruption of treatment after an adverse reaction 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 reaction 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.



Toxicity         Grade*         Action for patients greater         Action for patients less than than or equal to 45 kg              45 kg
Cytokine         Grade 3        Interrupt BLINCYTO until            Interrupt BLINCYTO until release                         resolved, then restart              resolved, then restart syndrome,                       BLINCYTO at 9 mcg/day.              BLINCYTO at 5 mcg/m2/day.
Tumor lysis                     Escalate to 28 mcg/day after        Escalate to 15 mcg/m2/day after syndrome                        7 days if the toxicity does not     7 days if the toxicity does not recur.                              recur.

Grade 4        Discontinue BLINCYTO                Discontinue BLINCYTO permanently.                        permanently.

Neurological     Convulsion Discontinue BLINCYTO                    Discontinue BLINCYTO toxicity                    permanently if more than one            permanently if more than one convulsion occurs.                      convulsion occurs.

Grade 3        Interrupt BLINCYTO until no         Interrupt BLINCYTO until no more than grade 1 (mild) and        more than grade 1 (mild) and for for at least 3 days, then restart   at least 3 days, then restart
BLINCYTO at 9 mcg/day.              BLINCYTO at 5 mcg/m2/day.
Escalate to 28 mcg/day after        Escalate to 15 mcg/m2/day after
7 days if the toxicity does not     7 days if the toxicity does not recur. For reinitiation,            recur. If the toxicity occurred at premedicate with a 24 mg dose       5 mcg/m2/day, or if the toxicity of dexamethasone. Then reduce       takes more than 7 days to dexamethasone step-wise over        resolve, discontinue BLINCYTO
4 days. If the toxicity occurred    permanently.
at 9 mcg/day, or if the toxicity takes more than 7 days to resolve, discontinue
BLINCYTO permanently.

Grade 4        Discontinue BLINCYTO                Discontinue BLINCYTO permanently.                        permanently.
Elevated liver   Grade 3        If clinically relevant, interrupt   If clinically relevant, interrupt enzymes                         BLINCYTO until no more than         BLINCYTO until no more than grade 1 (mild), then restart        grade 1 (mild), then restart
BLINCYTO at 9 mcg/day.              BLINCYTO at 5 mcg/m2/day.
Escalate to 28 mcg/day after        Escalate to 15 mcg/m2/day after
7 days if the toxicity does not     7 days if the toxicity does not recur.                              recur.

Grade 4        Consider discontinuing              Consider discontinuing BLINCYTO permanently.               BLINCYTO permanently.
Other            Grade 3        Interrupt BLINCYTO until no         Interrupt BLINCYTO until no clinically                      more than grade 1 (mild), then      more than grade 1 (mild), then relevant (as                    restart BLINCYTO at                 restart BLINCYTO at determined by                   9 mcg/day. Escalate to              5 mcg/m2/day. Escalate to treating                        28 mcg/day after 7 days if the      15 mcg/m2/day after 7 days if the physician)                      toxicity does not recur.            toxicity does not recur.
adverse reactions        Grade 4        Consider discontinuing              Consider discontinuing BLINCYTO permanently.               BLINCYTO permanently.
* Based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 is severe, and grade 4 is life-threatening.

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 analyzes, 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 analyzes, 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.

Pediatric 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 sections 4.8 and 5.1.

Method of administration

BLINCYTO is for intravenous use.
For instructions on the handling and preparation of the medicinal product before administration, see section 6.6.

Administer BLINCYTO as a continuous intravenous infusion delivered at a constant flow rate using an infusion pump over a period of up to 96 hours. The pump should be programmable, lockable, non-elastomeric, and have an alarm.

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 prepared BLINCYTO final infusion 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 
Administer prepared BLINCYTO final infusion solution using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding 0.2 micrometer in-line filter.

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.


The choice of the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes and the weight of the patient. 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.