Neupogen

Overdose

The effects of Neupogen overdosage have not been established. Discontinuation of Neupogen 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

30 months.

Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hours at 2 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 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Incompatibilities

Neupogen should not be diluted with saline solutions.

Diluted filgrastim may be adsorbed to glass and plastic materials.

This medicinal product must not be mixed with other products except those mentioned in 6.6.

List of excipients

Sodium Acetate*

Sorbitol (E420)

Polysorbate 80

Water for Injections

*Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide

Undesirable effects

a. Summary of the safety profile

The most serious adverse reactions that may occur during Neupogen treatment include: anaphylactic reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or leukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease.

The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain), anaemia, vomiting, and nausea. In clinical trials in cancer patients musculoskeletal pain was mild or moderate in 10%, and severe in 3% of patients.

b. Tabulated summary of adverse reactions

The data in the tables below describe adverse reactions reported from clinical trials and spontaneous reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

a See section c (Description of selected adverse reactions)

b There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (see section c)

c Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain

d Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPC mobilization

e Adverse events with higher incidence in Neupogen patients compared to placebo and associated with the sequelae of the underlying malignancy or cytotoxic chemotherapy

c. Description of selected adverse reactions

Hypersensitivity

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in post marketing experience. Overall, reports were more common after IV administration. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Neupogen should be permanently discontinued in patients who experience a serious allergic reaction.

Pulmonary adverse events

In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung disease, pulmonary oedema, and lung infiltration have been reported in some cases with an outcome of respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal.

Splenomegaly and Splenic rupture

Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. Some cases of splenic rupture were fatal.

Capillary leak syndrome

Cases of capillary leak syndrome have been reported with granulocyte colony-stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis.

Cutaneous vasculitis

Cutaneous vasculitis has been reported in patients treated with Neupogen. The mechanism of vasculitis in patients receiving Neupogen is unknown. During long term use cutaneous vasculitis has been reported in 2% of SCN patients.

Leukocytosis

Leukocytosis (WBC > 50 x 109/l) was observed in 41% of normal donors and transient thrombocytopenia (platelets < 100 x 109/l) following filgrastim and leukapheresis was observed in 35% of donors.

Sweets syndrome

Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients treated with Neupogen.

Pseudogout (chondrocalcinosis pyrophosphate)

Pseudogout (chondrocalcinosis pyrophosphate) has been reported in patients with cancer treated with Neupogen.

GvHD

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation.

d. Paediatric population

Data from clinical studies in paediatric patients indicate that the safety and efficacy of Neupogen are similar in both adults and children receiving cytotoxic chemotherapy suggesting no age-related differences in the pharmacokinetics of filgrastim. The only consistently reported adverse event was musculoskeletal pain‚ which is no different from the experience in the adult population.

There is insufficient data to further evaluate Neupogen use in paediatric subjects.

e. Other special populations

Geriatric Use

No overall differences in safety or effectiveness were observed between subjects over 65 years of age compared to younger adult (>18 years of age) subjects receiving cytotoxic chemotherapy and clinical experience has not identified differences in the responses between elderly and younger adult patients. There is insufficient data to evaluate Neupogen use in geriatric subjects for other approved Neupogen indications.

Paediatric SCN patients

Cases of decreased bone density and osteoporosis have been reported in paediatric patients with severe chronic neutropenia receiving chronic treatment with Neupogen.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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 Neupogen, 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

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Neupogen containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral blood neutrophil counts within twenty-four 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 durations 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 the 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 PBPC accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions.

Recipients of allogeneic PBPCs mobilised with Neupogen 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 GCSF 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 GCSF 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 μg/kg/day dose administered subcutaneously for 4 to 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 patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic neutropenia) induces a sustained increase in absolute neutrophil counts 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 medication. 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

Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous and 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 Neupogen 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 elimination half-lives. 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 10 ng/ml for 8 to 16 hours. The volume of distribution in blood is approximately 150 ml/kg.

Date of revision of the text

08 February 2018

Marketing authorisation holder

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

Special precautions for storage

Store at 2 to 8°C.

Accidental exposure to freezing temperatures does not adversely affect the stability of Neupogen.

Keep the container in the outer carton in order to protect from light.

Nature and contents of container

Package containing one or five vial(s) of 1 ml Neupogen solution for injection.

The vials are made from type I glass with rubber stoppers.

Not all pack sizes may be marketed.

Marketing authorisation number(s)

PL 16216/0038

Effects on ability to drive and use machines

Neupogen may have a minor influence on the ability to drive and use machines. Dizziness may occur following the administration of Neupogen.

Special precautions for disposal and other handling

If required, Neupogen 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.

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 20% human albumin solution Ph. Eur. added.

Neupogen contains no preservative. In view of the possible risk of microbial contamination, Neupogen vials are for single use only.

When diluted in 5% glucose solution, Neupogen is compatible with glass and a variety of plastics including PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.

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

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 15 March 1991

Date of latest renewal: 20 April 2008