Posology : מינונים

4.2      Posology and method of administration

StimoFil therapy should only be given in collaboration with an oncology centre which has experience in granulocyte-colony stimulating factor (G-CSF) treatment and hematology and has the necessary diagnostic facilities. The mobilization and apheresis procedures should be performed in collaboration with an oncology-hematology centre with acceptable experience in this field and where the monitoring of hematopoietic progenitor cells can be correctly performed.

Established cytotoxic chemotherapy

Posology
The recommended dose of filgrastim is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of StimoFil should not be administered less than 24 hours following cytotoxic chemotherapy. In randomised clinical trials, a subcutaneous dose of 230 microgram/m2/day (4.0 to 8.4 microgram/kg/day) was used.

Daily dosing with filgrastim should continue until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Following established chemotherapy for solid tumors, lymphomas, and lymphoid leukemias, it is expected that the duration of treatment required to fulfil these criteria will be up to 14 days. Following induction and consolidation treatment for acute myeloid leukemia the duration of treatment may be substantially longer (up to 38 days) depending on the type, dose and schedule of cytotoxic chemotherapy used.

In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1-2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim therapy should not be discontinued before the expected nadir has passed and the neutrophil count has recovered to the normal range. Premature discontinuation of filgrastim therapy, prior to the time of the expected neutrophil nadir, is not recommended.

In patients treated with myeloablative therapy followed by bone marrow transplantation 
The recommended starting dose of filgrastim is 1.0 MU/kg/day (10 micrograms/kg/day). The first dose of filgrastim should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion.

Once the neutrophil nadir has been passed, the daily dose of filgrastim should be titrated against the neutrophil response as follows:

Neutrophil Count                               Filgrastim dose adjustment 9
> 1.0 x 10 /L for 3 consecutive days           Reduce to 0.5 MU (5 µg) /kg/day Then, if ANC remains > 1.0 x 109/L for 3       Discontinue filgrastim more consecutive days
If the ANC decreases to < 1.0 x 109/L during the treatment period, the dose of filgrastim should be 
re-escalated according to the above steps
ANC = absolute neutrophil count

For Mobilization of peripheral blood progenitor cells (PBPC) in patients undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC transplantation 
The recommended dose of filgrastim for PBPC mobilization when used alone is 1.0 MU (10 µg)/kg/day for 5-7 consecutive days. The timing of leukapheresis: 1 or 2 leukaphereses on days 5 and 6 are often sufficient. In other circumstances, additional leukaphereses may be necessary. Filgrastim dosing should be maintained until the last leukapheresis.

The recommended dose of filgrastim for PBPC mobilization after myelosuppressive chemotherapy is 0.5 MU (5 µg)/kg/day given daily from the first day after completion of chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range.
Leukapheresis should be performed during the period when the ANC rises from < 0.5 x 109/L to > 5.0 x 109/L. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient.
In other circumstances, additional leukaphereses are recommended.

For the mobilization of PBPCs in normal donors prior to allogeneic PBPC transplantation 
For PBPC mobilization in normal donors, filgrastim should be administered at 1.0 MU (10 µg)/kg/day for 4 - 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if needed in order to collect 4 x 106 CD34+ cells/kg recipient bodyweight.

In patients with severe chronic neutropenia (SCN)

Congenital neutropenia: The recommended starting dose is 1.2 MU (12 µg)/kg/day as a single dose or in divided doses.

Idiopathic or cyclic neutropenia: The recommended starting dose is 0.5 MU (5 µg)/kg/day as a single dose or in divided doses.

Dose adjustments: Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has reached and can be maintained at more than 1.5 x 109/L. When the response has been obtained, the minimal effective dose to maintain this level should be established. Long-term daily administration is required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose may be doubled or halved depending upon the patient's response.
Subsequently, the dose may be individually adjusted every 1-2 weeks to maintain the average neutrophil count between 1.5 x 109/L and 10 x 109/L. A faster schedule of dose escalation may be considered in patients presenting with severe infections. In clinical studies, 97% of patients who responded had a complete response at doses of ≤ 24 µg/kg/day. The long-term safety of administration of filgrastim at doses above 24 µg/kg/day in patients with SCN has not been established.

In patients with HIV infection

For reversal of neutropenia:
The recommended starting dose of filgrastim is 0.1 MU (1 µg)/kg/day, given daily with titration up to a maximum of 0.4 MU (4 µg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC > 2.0 x 109/L). In clinical studies, more than 90% of patients responded at these doses, achieving a reversal of neutropenia in a median of 2 days.

In a small number of patients (< 10%), doses up to 1.0 MU (10 µg)/kg/day were required to achieve reversal of neutropenia.

For maintenance of normal neutrophil counts:

When reversal of neutropenia has been achieved, the minimal effective dose to maintain a normal neutrophil count should be established. Initial dose adjustment to alternate day dosing with 30 MU (300 µg)/day is recommended. Further dose adjustment may be necessary, as determined by the patient's ANC, to maintain the neutrophil count at > 2.0 x 109/L. In clinical studies, dosing with 30 MU (300 µg)/day on 1 - 7 days per week was required to maintain the ANC > 2.0 x 109/L, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC > 2.0 x 109/L.

Special populations

Elderly
Clinical trials with filgrastim have included a small number of elderly patients but special studies have not been performed in this group and therefore specific posology recommendations cannot be made.

Patients with renal impairment

Studies of filgrastim in patients with severe impairment of renal or hepatic function demonstrate that it exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals.
Dose adjustment is not required in these circumstances.

Pediatric patients in the SCN and cancer settings

Sixty-five percent of patients studied in a SCN trial program were under 18 years of age. The efficacy of the treatment was clear for this age group, which included most patients with congenital neutropenia. There were no differences in the safety profiles for pediatric patients treated for SCN.

Data from clinical studies in pediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy.

The dosage recommendations in pediatric patients are the same as those in adults receiving myelosuppressive cytotoxic chemotherapy.

Method of administration

Established cytotoxic chemotherapy
Filgrastim may be administered as a daily subcutaneous injection or alternatively as a daily intravenous infusion diluted in glucose 50 mg/ml (5%) solution over 30 minutes. For further instructions on dilution prior to infusion see section 6.6. The subcutaneous route is preferred in most cases. There is some evidence from a study of single dose administration that intravenous dosing may shorten the duration of effect. The clinical relevance of this finding to multiple dose administration is not clear. The choice of route should depend on the individual clinical circumstance.

Patients treated with myeloablative therapy followed by bone marrow transplantation Filgrastim is administered as an intravenous short-term infusion over 30 minutes or as a subcutaneous or intravenous continuous infusion over 24 hours, in each case after dilution in 20 ml of glucose 50 mg/ml (5%) solution. For further instructions on dilution with glucose 50 mg/ml (5%) solution prior to infusion see section 6.6.

In patients with Mobilization of PBPC
Filgrastim for PBPC mobilization when used alone:

Filgrastim may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. For infusions filgrastim should be diluted in 20 ml of 5% glucose solution (see section 6.6).

Filgrastim for PBPC mobilization after myelosuppressive chemotherapy: 
Filgrastim should be given by subcutaneous injection.

For the mobilization of PBPCs in normal donors prior to allogeneic PBPC transplantation Filgrastim should be given by subcutaneous injection.

In patients with SCN
Congenital, idiopathic or cyclic neutropenia; filgrastim should be given by subcutaneous injection.

In patients with HIV infection
For the reversal of neutropenia and maintenance of normal neutrophil counts in patients with HIV infection, filgrastim is administered subcutaneously.