Neulastim 6mg / 0.6ml Injection

Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

NEULASTIM u00ae therapy should be initiated and supervised by physicians experienced in oncology and/or haematology.

Posology

One 6 mg dose (a single pre-filled syringe) of NEULASTIM u00ae is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy.

Special populations

Paediatric population
The safety and efficacy of NEULASTIM u00ae in children has not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Patients with renal impairment
No dose change is recommended in patients with renal impairment, including those with end-stage renal disease.

Method of administration
NEULASTIM u00ae is injected subcutaneously via a pre-filled syringe for manual administration. The manually administered injections should be given into the thigh, abdomen or upper arm. For instructions on handling of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Traceability
In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs the trade name of the administered product should be clearly recorded in the patient file.

Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for pegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia (AML) (see section 5.1). However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should be used with caution in this patient population.

G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro. The safety and efficacy of pegfilgrastim 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 AML. The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established.

The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.

Pulmonary adverse events
Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk (see section 4.8). 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 pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given (see 4.8).

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.

Capillary leak syndrome
Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see 4.8).

Splenomegaly and Splenic Rupture
Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see 4.8). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal / or shoulder tip pain.

Thrombocytopenia and anaemia
Treatment with pegfilgrastim 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. Special care should be taken when administering single or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.

Myelodysplastic syndrome and acute myeloid leukaemia in breast and lung cancer patients
In the post-marketing observational study setting, pegfilgrastim in conjunction with chemotherapy and/or radiotherapy has been associated with development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) in breast and lung cancer patients (see section 4.8). Monitor breast and lung cancer patients for signs and symptoms of MDS/AML.

Sickle cell anaemia
Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease (see 4.8). Therefore, physicians should use caution when prescribing pegfilgrastim in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicine with splenic enlargement and vaso-occlusive crisis.

Leukocytosis
White blood cell (WBC) counts of 100 x 10 9 /l or greater have been observed in less than 1 % of patients receiving pegfilgrastim. No adverse events directly attributable to this degree of leukocytosis have been reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicine. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 x 10 9 /l after the expected nadir, this medicine should be discontinued immediately.

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. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days.

Stevens-Johnson syndrome
Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time.

Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present.

Aortitis
Aortitis has been reported in patients receiving G-CSF such as pegfilgrastim and the symptoms experienced included fever, abdominal pain, malaise, back pain and inflammatory markers (e.g. c-reactive protein and white blood cell count) were raised. In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8.

Other warnings
The safety and efficacy of NEULASTIM u00ae for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated. The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone-imaging results.

Sorbitol
The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

Sodium
This medicine contains less than 1 mmol sodium (23 mg) per 6 mg dose, that is to say essentially u2018sodium-freeu2019.

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, NEULASTIM u00ae should be administered approximately 24 hours after administration of cytotoxic chemotherapy. In clinical studies, NEULASTIM u00ae has been safely administered 14 days before chemotherapy. Concomitant use of NEULASTIM u00ae with any chemotherapy agent has not been evaluated in patients. In animal models, concomitant administration of NEULASTIM u00ae and 5-fluorouracil (5-FU) or other anti metabolites has been shown to potentiate myelosuppression. Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical studies. The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful. The safety and efficacy of NEULASTIM u00ae have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression e.g. nitrosoureas. Specific interaction or metabolism studies have not been performed, however clinical studies have not indicated an interaction of NEULASTIM u00ae with any other medicinal products.

Pregnancy
There are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Pegfilgrastim is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding
There is insufficient information on the excretion of pegfilgrastim/metabolites in human milk, a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegfilgrastim therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility
Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area) (see section 5.3).

NEULASTIM u00ae has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile
The most frequently reported adverse reactions were bone pain (very common [u2265 1/10]) and musculoskeletal pain (common [u2265 1/100 to < 1/10]). Bone pain was generally of mild to moderate severity, transient and could be controlled in most patients with standard analgesics. Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythaema, flushing, and hypotension, occurred on initial or subsequent treatment with pegfilgrastim (uncommon [u2265 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving pegfilgrastim (uncommon) (see section 4.4).

Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (u2265 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration of G-CSFs; (see section 4.4 and section u201cDescription of selected adverse reactionsu201d below. Splenomegaly, generally asymptomatic, is uncommon. Splenic rupture including some fatal cases is uncommonly reported following administration of pegfilgrastim (see section 4.4). Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in respiratory failure or ARDS, which may be fatal (see section 4.4). Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell disease (uncommon in sickle cell patients) (see section 4.4).

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

Single doses of 300 u03bcg/kg have been administered subcutaneously to a limited number of healthy volunteers and patients with non-small cell lung cancer without serious adverse effects. The adverse events were similar to those in subjects receiving lower doses of pegfilgrastim.