Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Ratiopharm GmbH, Graf-Arco-Straße 3, 89079 Ulm, Germany
Ratiograstim 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 filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
Ratiograstim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).
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 Ratiograstim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
Ratiograstim 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.
Filgrastim 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 MIU (5 μg)/kg/day. The first dose of filgrastim should be administered at least 24 hours after cytotoxic chemotherapy. In randomised clinical trials, a subcutaneous dose of 23 MIU (230 μg)/m²/day (4.0 to 8.4 μg/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 to 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.
Filgrastim may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 5% glucose solution for infusion given over 30 minutes (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.
The recommended starting dose of filgrastim is 1.0 MIU (10 μg)/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 MIU (5 µg)/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
Filgrastim may be given as a 30 minute or 24 hour intravenous infusion or given by continuous 24 hour subcutaneous infusion. Filgrastim should be diluted in 20 mL of 5% glucose solution for infusion (see section 6.6).
The recommended dose of filgrastim for PBPC mobilisation when used alone is 1.0 MIU (10 μg)/kg/day for 5 to 7 consecutive days. Timing of leukapheresis: 1 or 2 leukapheresis on days 5 and 6 are often sufficient. In other circumstances, additional leukapheresis 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 MIU (5 μg)/kg/day 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 leukapheresis are recommended.
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 for infusion (see section 6.6).
Filgrastim should be given by subcutaneous injection.
For PBPC mobilisation in normal donors, filgrastim should be administered at 1.0 MIU (10 μg)/kg/day for 4 to 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.
Filgrastim should be given by subcutaneous injection.
The recommended starting dose is 1.2 MIU (12 μg)/kg/day as a single dose or in divided doses.
The recommended starting dose is 0.5 MIU (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 to 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 trials, 97% of patients who responded had a complete response at doses of ≤2.4 MIU (24 μg)/kg/day. The long-term safety of filgrastim administration above 2.4 MIU (24 μg)/kg/day in patients with SCN has not been established.
Filgrastim should be given by subcutaneous injection.
The recommended starting dose of filgrastim is 0.1 MIU (1 μg)/kg/day with titration up to a maximum of 0.4 MIU (4 μg)/kg/day until a normal neutrophil count is reached and can be maintained (ANC >2.0 × 109/L). In clinical studies, >90% of patients responded at these doses, achieving reversal of neutropenia in a median of 2 days.
In a small number of patients (<10%), doses up to 1.0 MIU (10 μg)/kg/day were required to achieve reversal of neutropenia.
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 MIU (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 MIU (300 μg)/day on 1 to 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.
Filgrastim should be given by subcutaneous injection.
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 dosage 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 the patients studied in the SCN trial programme were under 18 years of age. The efficacy of 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.
The effects of filgrastim overdosage 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.
30 months.
After dilution: 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).
Within its shelf-life and for ambulatory use, the product may be removed from the refrigerator (2°C-8°C) and stored at a temperature up to 25°C for one single period of up to 4 days. If not used within 4 days, the product may be returned to the refrigerator (2°C-8°C) up to the expiry date. Dispose of syringes if stored above 8°C for more than 4 days.
For storage conditions after dilution of the medicinal product, see section 6.3.
Type I glass pre-filled syringe with a permanently attached stainless steel needle with or without safety device to prevent needle stick injury and re-use.
Ratiograstim 30 MIU/0.5 mL solution for injection/infusion: Packs containing 1, 5 or 10 pre-filled syringes with 0.5 mL solution or multipacks containing 10 (2 packs of 5) pre-filled syringes with 0.5 mL solution.
Ratiograstim 48 MIU/0.8 mL solution for injection/infusion: Packs containing 1, 5 or 10 pre-filled syringes with 0.8 mL solution or multipacks containing 10 (2 packs of 5) pre-filled syringes with 0.8 mL solution.
Not all pack sizes may be marketed.
If required, Ratiograstim may be diluted in glucose 50 mg/mL (5%) solution for infusion.
Dilution to a final concentration less than 0.2 MIU (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.
For patients treated with filgrastim diluted to concentrations below 1.5 MIU (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 MIU (300 μg) should be given with 0.2 mL of 200 mg/mL (20%) human albumin solution added.
When diluted in glucose 50 mg/mL (5%) solution for infusion, Ratiograstim is compatible with glass and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.
Ratiograstim does not contain any preservative. In view of the possible risk of microbial contamination, Ratiograstim syringes are for single use only.
Accidental exposure to freezing temperatures does not adversely affect the stability of Ratiograstim.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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