Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Accord Healthcare S.L.U., World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain
Accofil is indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) and for the reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia. The safety and efficacy of Accofil are similar in adults and children receiving cytotoxic chemotherapy.
Accofil is indicated for the mobilisation of peripheral blood progenitor cells (PBPCs).
In patients, children or adults with severe congenital, cyclic, or idiopathic neutropenia with an absolute neutrophil count (ANC) of ≤0.5 × 109/L, and a history of severe or recurrent infections, long term administration of Accofil is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
Accofil is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 × 109/L) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.
Accofil therapy should only be given in collaboration with an oncology centre which has experience in granulocyte-colony stimulating factor (G-CSF) treatment and haematology and has the necessary diagnostic facilities. The mobilisation and apheresis procedures should be performed in collaboration with an oncology-haematology centre with acceptable experience in this field and where the monitoring of haematopoietic progenitor cells can be correctly performed.
The recommended dose of filgrastim is 0.5 MU/kg/day (5 micrograms/kg/day). The first dose of Accofil 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 tumours, lymphomas, and lymphoid leukaemias, 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 leukaemia 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.
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 |
|---|---|
| >1.0 × 109/L for 3 consecutive days | Reduce to 0.5 MU (5μg)/kg/day |
| Then, if ANC remains >1.0 × 109/L for 3 more consecutive days | Discontinue filgrastim |
| If the ANC decreases to <1.0 × 109/L during the treatment period, the dose of filgrastim should be re-escalated according to the above steps | |
ANC = absolute neutrophil count
The recommended dose of filgrastim for PBPC mobilisation 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 mobilisation 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 × 109/L to >5.0 × 109/L. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient. In other circumstances, additional leukaphereses are recommended.
For PBPC mobilisation 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 × 106 CD34+ cells/kg recipient bodyweight.
The recommended starting dose is 1.2 MU (12 μg)/kg/day as a single dose or in divided doses.
The recommended starting dose is 0.5 MU (5 μg)/kg/day as a single dose or in divided doses.
Filgrastim should be administered daily by subcutaneous injection until the neutrophil count has reached and can be maintained at more than 1.5 × 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 × 109/L and 10 × 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.
For reversal of neutropenia: The recommended starting dose of filgrastim is 0.1 MU (1 μg)/kg/day, 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 × 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 × 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 × 109/L, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC >2.0 × 109/L.
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.
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.
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 paediatric patients treated for SCN.
Data from clinical studies in paediatric patients indicate that the safety and efficacy of filgrastim are similar in both adults and children receiving cytotoxic chemotherapy.
The dosage recommendations in paediatric patients are the same as those in adults receiving myelosuppressive 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.
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.
Filgrastim may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. For infusions filgrastim should be diluted in 20ml of 5% glucose solution (see section 6.6).
Filgrastim
should be given by subcutaneous injection.
Filgrastim should be given by subcutaneous injection.
Congenital, idiopathic or cyclic neutropenia; filgrastim should be given by subcutaneous injection.
For the reversal of neutropenia and maintenance of normal neutrophil counts in patients with HIV infection, filgrastim is administered subcutaneously.
The effects of Accofil overdose have not been established. Discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal levels in 1 to 7 days.
36 months.
Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hours at 2°C to 8°C. From a microbiological point of view, the product 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 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C–8°C). Do not freeze.
Accidental one-time exposure to freezing temperatures does not adversely affect the stability of Accofil. If exposure has been greater than 24 hours or frozen more than once then Accofil should NOT be used.
Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 days. At the end of this period, the product should not be put back in the refrigerator and should be disposed of.
Keep the syringe in the outer carton in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
Pre-filled syringe with injection needle, with or without a needle safety guard. Package containing one, three, five, seven or ten pre-filled syringe (s), with or without blister and alcohol swabs. The packs without blister are without needle safety guard. The blister packs are for individual syringes with prefixed needle safety guard. The pre-filled syringes are made from Type I glass with a permanently attached stainless steel needle in the tip and have 1/40 printed markings for graduations from 0.1 mL to 1 mL on the barrel. The needle cover of the pre-filled syringe contains dry natural rubber (see section 4.4). Each pre-filled syringe contains 0.5 ml solution.
Not all pack sizes may be marketed.
If required, Accofil may be diluted in 5% glucose. Dilution to a final concentration less than 0.2 MU (2 μg) per ml is not recommended at any time.
The solution should be visually inspected prior to use. Only clear solutions without particles should be used. Do not shake.
For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 μg) per ml, human serum albumin (HSA) should be added to a final concentration of 2 mg/ml.
Example: In a final injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 μg) should be given with 0.2 ml of 200 mg/ml (20%) human albumin solution added.
Accofil contains no preservative. In view of the possible risk of microbial contamination, Accofil pre-filled syringes are for single use only.
When diluted in 5% glucose, Accofil is compatible with glass and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.
The needle safety guard covers the needle after injection to prevent needle stick injury. This does not affect normal operation of the syringe. Depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. While maintaining pressure on the plunger, remove the syringe from the patient. The needle safety guard will cover the needle when releasing the plunger.
Administer the dose as per standard protocol.
Any unused product or waste material should be disposed of in accordance with local requirements.
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