2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 NEW ZEALAND DATA SHEET Neulastim New Zealand Data Sheet Page 1 of 16 1. NEULASTIM (6 mg in mL solution for injection) Neulastim 6 mg in mL solution for injection (pre-filled syringe) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 6 mg of pegfilgrastim in mL (10 mg/mL*) solution for injection. The concentration is 20 mg/mL if the PEG moiety is included. * Based on protein only. Pegfilgrastim is composed of filgrastim (recombinant methionyl human G-CSF) with a 20 kDa polyethylene glycol (PEG) molecule covalently bound to the N-terminal methionine residue. Filgrastim is produced by recombinant DNA technology in E coli (K12). Excipient(s) with known effect Each pre-filled syringe contains 30 mg sorbitol (E420).

2 Each pre-filled syringe contains less than 1 mmol (23 mg) sodium For the full list of excipients, see section 3. PHARMACEUTICAL FORM Neulastim is a clear, colourless solution for injection in a pre-filled syringe. 4. CLINICAL PARTICULARS Therapeutic indications Reduction in the duration of neutropenia, the incidence of febrile neutropenia and the incidence of infection as manifested by febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). Dose and method of administration Neulastim therapy should be initiated and supervised by physicians experienced in oncology and/or haematology. Dose One 6 mg dose (a single pre-filled syringe) of Neulastim is recommended for each chemotherapy cycle, administered as a subcutaneous injection approximately 24 hours following cytotoxic chemotherapy.

3 NEW ZEALAND DATA SHEET Neulastim New Zealand Data Sheet Page 2 of 16 Paediatric population The safety and efficacy of Neu lastim in children aged below 18 years have not yet been established. Currently available data are described in section but no recommendation on a dosage can be made. Method of administration Subcutaneous injection. For instructions on handling the medicine before administration, see section Contraindications Hypersensitivity to pegfilgrastim, filgrastim, E. coli-derived proteins, or to any excipients listed in section . Special warnings and precautions for use General Neulastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens. The safety and efficacy of Neulastim have not been investigated in patients receiving high dose chemotherapy.

4 Hypersensitivity Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have been reported in patients treated with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. Use in leukaemia and myelodysplasia Limited clinical data suggest that the effect on time to recovery of severe neutropenia between pegfilgrastim and filgrastim is comparable in patients with de novo acute myeloid leukaemia (see section ). However, the long-term effects of Neulastim have not been established in acute myeloid leukaemia (AML); therefore, it should be used with caution in this patient population.

5 Granulocyte-colony stimulating factor can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro. NEW ZEALAND DATA SHEET Neulastim New Zealand Data Sheet Page 3 of 16 The safety and efficacy of Neulastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia. The safety and efficacy of Neulastim administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established.

6 Acute Respiratory Distress Syndrome The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS). In such circumstances Neulastim should be discontinued at the discretion of the physician and the appropriate treatment given. Splenic Rupture and Splenomegaly Splenic rupture, in some cases fatal, has been reported following administration of Neulastim. Spleen size should be carefully monitored. Patients receiving pegfilgrastim who report left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.

7 Trea tment with Neulastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Capillary leak syndrome Capillary leak syndrome, characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration, has been reported very rarely. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate medical attention. Sickle Cell Crisis Sickle cell crisis has been associated with the use of Neulastim in patients with sickle cell trait or sickle cell disease. Physicians should use caution when prescribing the use of Neulastim in patients with sickle cell trait or sickle cell disease.

8 NEW ZEALAND DATA SHEET Neulastim New Zealand Data Sheet Page 4 of 16 The safety and efficacy of Neulastim for the mobilisation of blood progenitor cells in patients has not been adequately evaluated. Glomerulonephritis Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Considering all sources of data on immunogenicity, rates of generation of antibodies against pegfilgrastim are generally low. Binding antibodies do develop as expected with all biologics however were not associated with neutralising antibodies and adverse clinical consequences.

9 The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to pegfilgrastim with the incidence of antibodies to other products may be misleading. Aortitis Aortitis has been reported in patients receiving Neulastim and may present with generalised signs and symptoms such as fever and increased inflammatory markers. Consider aortitis in patients who develop these signs and symptoms without known aetiology.

10 Laboratory tests White blood cell counts of 100 x 109/L or greater have been observed in less than 1% of patients receiving Neulastim. No adverse events directly attributable to this degree of leucocytosis have been reported. Such elevation in White Blood Cells is transient, typi cally seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of Neulastim. Monitoring of Complete Blood Count (CBC) during Neulastim therapy is recommended. NEW ZEALAND DATA SHEET Neulastim New Zealand Data Sheet Page 5 of 16 Paediatric population There are insufficient data to recommend the use of Neulastim in children and adolescents under 18 years of age. Use in the elderly patients See section Renal impairment See section Hepatic impairment See section Interaction with other medicines and other forms of interaction Cytotoxic chemotherapy Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy Neulastim should be administered approximately 24 hours after administration of cytotoxic chemotherapy.