Accofil

Accofil 30 MU/0.5 ml solution for injection or infusion in pre-filled syringe

Overdose

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.

Shelf life

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.

Incompatibilities

Accofil must not be diluted with saline solutions.

Diluted filgrastim may be adsorbed to glass and plastic materials.

List of excipients

Acetic acid glacial

Sodium hydroxide

Sorbitol (E420)

Polysorbate 80

Water for injections

Preclinical safety data

Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed changes attributable to the expected pharmacological actions including increases in leukocytes, myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These changes all reversed after discontinuation of treatment.

Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous (80 µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was maternally toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size and fetal weight were observed.

Based on reported data for another filgrastim product similar to Accofil, comparable findings plus increased fetal malformations were observed at 100 µg/kg/day, a maternally toxic dose which corresponded to a systemic exposure of approximately 50-90 times the exposures observed in patients treated with the clinical dose of 5 µg/kg/day. The no observed adverse effect level for embryo-fetal toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure of approximately 3-5 times the exposures observed in patients treated with the clinical dose.

In pregnant rats, no maternal or fetal toxicity was observed at doses up to 575 µg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external differentiation and growth retardation (>20 µg/kg/day) and slightly reduced survival rate (100 µg/kg/day).

Filgrastim had no observed effect on the fertility of male or female rats.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: cytokines ATC code: L03AA02

Accofil is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Pharmacodynamic effects

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Accofil containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some SCN patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and basophils relative to baseline; some of these patients may present with eosinophilia or basophilia already prior to treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating neutrophil counts decrease by 50% within 1 to 2 days, and to normal levels within 1 to 7 days.

Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone marrow transplantation. The incidence of fever and documented infections were not reduced in either setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.

Use of filgrastim, either alone, or after chemotherapy, mobilises haematopoietic progenitor cells into peripheral blood. These autologous PBPCs may be harvested and infused after high-dose cytotoxic therapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPCs accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions. Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery when compared with allogeneic bone marrow transplantation.

One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including the results of nine prospective randomized trials, 8 retrospective studies and 1 case-controlled study, did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related mortality.

aAnalysis includes studies involving BM transplant during this period; some studies used GM-CSF

bAnalysis includes patients receiving BM transplant during this period

Use of filgrastim for the mobilisation of PBPCs in normal donors prior to allogeneic PBPC transplantation

In normal donors, a 10 micrograms/kg/day dose administered subcutaneously for 4 - 5 consecutive days allows a collection of > 4 x 106 CD34+ cells/kg recipient body weight in the majority of the donors after two leukaphereses.

Use of filgrastim in adults with SCN (severe congenital, cyclic, and idiopathic neutropenia) induces a sustained increase in ANCs in peripheral blood and a reduction of infection and related events.

Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive treatments. There is no evidence that patients with HIV infection treated with filgrastim show an increase in HIV replication.

As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.

Pharmacokinetic properties

Absorption

Following subcutaneous administration of recommended doses, serum concentrations were maintained above10 ng/ml for 8 - 16 hours.

Distribution

The volume of distribution in blood is approximately 150 ml/kg.

Elimination

Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous or intravenous administration. The serum elimination half-life of filgrastim is approximately 3.5 hours, with a clearance rate of approximately 0.6 ml/min/kg. Continuous infusion with Accofil over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no evidence of drug accumulation and comparable half-lives.

Linearity

There is a positive linear correlation between the dose and the serum concentration of filgrastim, whether administered intravenously or subcutaneously. Following subcutaneous administration of recommended doses , serum concentrations were maintained above 10ng/ml for 8 to 16 hours. The volume of distribution in blood is approximately 150ml/kg.

Date of revision of the text

25/05/2018

Marketing authorisation holder

Accord Healthcare Limited

Sage House, 319 Pinner Road

North Harrow,

Middlesex, HA1 4HF

United Kingdom

Special precautions for storage

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.

Nature and contents of container

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. Each pre-filled syringe contains 0.5 ml solution.

Not all pack sizes may be marketed.

Marketing authorisation number(s)

EU/1/14/946/001

EU/1/14/946/002

EU/1/14/946/005

EU/1/14/946/006

EU/1/14/946/007

EU/1/14/946/008

EU/1/14/946/009

EU/1/14/946/010

EU/1/14/946/017

Special precautions for disposal and other handling

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.

Using the pre-filled syringe with a needle safety guard

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.

Using the pre-filled syringe without a needle safety guard

Administer the dose as per standard protocol.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

Date of first authorisation/renewal of the authorisation

Date of first authorization: 18.09.2014