英文药名: Neulasta (Pegfilgrastim Prefilled Syringe)

中文药名: 非格司亭注射溶液/预充式注射器

生产厂家: Roche Pharmaceuticals
药品简介
Pegfilgrastim是一种人造蛋白质，刺激称为中性粒细胞的白细胞在身体里生长。白血细胞帮助人体抵抗感染的危害。
Pegfilgrastim用于治疗白细胞减少，治疗某些接受癌症化疗引起的白血球缺乏。也用在除了骨髓癌的其他癌症。
非格司亭的长效制剂Neulasta（Pegfilgrastim）于2002年1月获得批准。其适应证为减少与化疗引起的中性粒细胞减少症有关的感染发生率。这种药的独特之处为每个化疗周期只须注射一次。改变了安进公司最初的此类药品Neupogen（Filgrastim）的复杂用药方式，Neupogen需要在每个化疗周期结束后的至多两周内每天注射，约一半的患者须要注射10天以上。
Neulasta每个化疗疗程只用一次，减少了频繁注射给患者带来的痛苦以及医生与患者相聚带来感染的几率，也不用在化疗期间由于严重的感染疾病而频繁中断治疗。现在通过审批表明成千上万的化疗患者可以在每一轮化疗出现感染并发症之前使用Neulasta进行保护，从而减少了化疗风险。''Neulasta Neulasta(TM)是一种蛋白质，它可以刺激抗感染的白细胞(中性粒细胞)的产生。而中性粒细胞正是化疗的细胞毒性作用的对象。
由于在Neulasta中加入了聚乙二醇（PEG）增大其分子，使得它在体内的清除率减慢，半衰期大大延长。 因此在每轮化疗中只要注射一次便可。
Neulasta具有自我调节机制（中性粒细胞介导的清除作用），当患者中性粒细胞减少时，药物将一直存在于血液中。当中性粒细胞恢复正常时，它将会很快被清除掉。临床试验方面的证据 Neulasta的两个中心的3期临床试验显示，单剂量的Neulasta注射与平均为11天的NEUPOGEN (5mcg/kg/day)注射以后的保护感染的作用相比，不但明显地缩短了中性粒细胞减少症的持续时间，而且也减少了伴发的发热症状。
对310名乳腺癌患者给予Neulasta 100 mcg/kg的注射量，对157名患者给予了Neulasta 6mg的注射量。这项随机双盲试验是在接受4个疗程阿霉素(doxorubicin)和紫衫萜(docetaxel)化疗的乳腺癌患者中进行的。
Neulasta ®应冷藏贮存在2℃到8 ° C（36 °至46 ° F）下; 注射器应尽量避光，直到使用时。Neulasta预充式注射剂只能允许达到室温最多48小时之久。

NEULASTA 6mg solution for injection
1. Name of the medicinal product
Neulasta 6 mg solution for injection.
2. Qualitative and quantitative composition
Each pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 ml solution for injection. The concentration is 10 mg/ml based on protein only**.
*Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG).
** The concentration is 20 mg/ml if the PEG moiety is included.
The potency of this product should not be compared to the potency of another pegylated or non-pegylated protein of the same therapeutic class. For more information, see section 5.1
Excipient(s) with known effect:
Each pre-filled syringe contains 30 mg sorbitol (E420)
Each pre-filled syringe contains less than 1 mmol (23 mg) sodium (see section 4.4).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for injection.
Clear, colourless solution for injection.
4. Clinical particulars
4.1 Therapeutic indications
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).
4.2 Posology and method of administration
Neulasta 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 Neulasta is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy.
Method of administration
Neulasta is injected subcutaneously. The 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.
Paediatric population
The safety and efficacy of Neulasta 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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and precautions for use
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 (see section 5.1). However, the long-term effects of Neulasta have not been established in acute myeloid leukaemia; therefore, it should be used with caution in this patient population.
Granulocyte-colony stimulating factor 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 Neulasta have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary Acute Myeloid Leukaemia (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 Neulasta administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established.
The safety and efficacy of Neulasta 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
Uncommon (≥1/1,000 to < 1/100) 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 Neulasta should be discontinued at the discretion of the physician and the appropriate treatment given (see section 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 hemoconcentration. 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 section 4.8).
Splenomegaly and splenic rupture
Uncommon but generally asymptomatic cases of splenomegaly and uncommon cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 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 pain or shoulder tip pain.
Thrombocytopenia and anaemia
Treatment with Neulasta 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.
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 section 4.8). Therefore, physicians should use caution when prescribing Neulasta 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 109/l or greater have been observed in less than 1% of patients receiving Neulasta. 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 109/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 Neulasta. Permanently discontinue Neulasta in patients with clinically significant hypersensitivity. Do not administer Neulasta 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.
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.
The safety and efficacy of Neulasta 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.
Neulasta contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Neulasta contains less than 1 mmol (23 mg) sodium per 6 mg dose, i.e. essentially 'sodium-free'.
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.
4.5 Interaction with other medicinal products and other forms of interaction
Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, Neulasta should be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical trials, Neulasta has been safely administered 14 days before chemotherapy. Concomitant use of Neulasta with any chemotherapy agent has not been evaluated in patients. In animal models concomitant administration of Neulasta and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression.
Possible interactions with other haematopoietic growth factors and cytokines have not been specifically investigated in clinical trials.
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 Neulasta 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 trials have not indicated an interaction of Neulasta with any other medicinal products.
4.6 Fertility, pregnancy and lactation
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). Neulasta is not recommended during pregnancy and in women of childbearing potential not using contraception.
Women who become pregnant during Neulasta treatment are encouraged to enrol in Amgen's Pregnancy Surveillance Programme. Contact details are provided in section 6 of the Package leaflet.
Breast-feeding
There is insufficient information on the excretion of Neulasta / 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 Neulasta therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Women who are breast-feeding during Neulasta treatment are encouraged to enrol in Amgen's Lactation Surveillance programme. Contact details are provided in section 6 of the Package leaflet.
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).
4.7 Effects on ability to drive and use machines
Neulasta has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and musculoskeletal pain (common). 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 Neulasta (uncommon [≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving Neulasta (uncommon) (see section 4.4).
Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported as uncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration of granulocyte colony-stimulating factors; see section 4.4 and section “Description of selected adverse reactions” 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 Acute Respiratory Distress Syndrome (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.

MedDRA system organ class	Adverse reactions
	Very common (≥ 1/10)	Common (≥ 1/100 to < 1/10)	Uncommon (≥ 1/1,000 to < 1/100)	Rare (≥ 1/10,000 to < 1/1,000)	Very rare (< 1/10,000)
Blood and lymphatic system disorders		Thrombocytopenia1 Leukocytosis1	Sickle cell crisis2; Splenomegaly2; Splenic rupture2
Immune system disorders			Hypersensitivity reactions; Anaphylaxis
Metabolism and nutrition disorders			Elevations in uric acid
Nervous system disorders	Headache1
Vascular disorders			Capillary leak syndrome1
Respiratory, thoracic and mediastinal disorders			Acute Respiratory Distress Syndrome2; Pulmonary adverse reactions (interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis)
Gastrointestinal disorders	Nausea1
Skin and subcutaneous tissue disorders			Sweet's syndrome (acute febrile dermatosis)1,2; Cutaneous vasculitis1,2
Musculoskeletal and connective tissue disorders	Bone pain	Musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculo-skeletal pain, neck pain)
General disorders and administrative site conditions		Injection site pain1 Non-cardiac chest pain	Injection site reactions2
Investigations			Elevations in lactate dehydrogenase and alkaline phosphatase1; Transient elevations in LFT's for ALT or AST1
Renal and urinary disorders			Glomerulonephritis2

1 See section “Description of selected adverse reactions” below.
2 This adverse reaction was identified through post-marketing surveillance but not observed in randomised, controlled clinical trials in adults. The frequency category was estimated from a statistical calculation based upon 1576 patients receiving Neulasta in nine randomized clinical trials.
Description of selected adverse reactions
Uncommon cases of Sweet's syndrome have been reported, although in some cases underlying haematological malignancies may play a role.
Uncommon events of cutaneous vasculitis have been reported in patients treated with Neulasta. The mechanism of vasculitis in patients receiving Neulasta is unknown.
Injection site reactions, including injection site erythaema (uncommon (≥ 1/1000 to < 1/100)) as well as injection site pain (common events ≥ 1/100 to < 1/10) have occurred on initial or subsequent treatment with Neulasta.
Common (≥ 1/100 to < 1/10) cases of leukocytosis (White Blood Count [WBC] > 100 x 109/l) have been reported (see section 4.4).
Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were uncommon in patients receiving Neulasta following cytotoxic chemotherapy.
Nausea and headaches were very commonly observed in patients receiving chemotherapy.
Uncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST (aspartate aminotransferase), have been observed in patients after receiving pegfilgrastim following cytotoxic chemotherapy. These elevations are transient and return to baseline.
Common cases of thrombocytopenia have been reported.
Cases of capillary leak syndrome have been reported in the post marketing setting with granulocyte colony-stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis (see section 4.4).
Paediatric population
The experience in children is limited. A higher frequency of serious adverse reactions in younger children aged 0-5 years (92%) has been observed compared to older children aged 6-11 and 12-21 years respectively (80% and 67%) and adults. The most common adverse reaction reported was bone pain (see section 5.1 and 5.2).
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:
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Single doses of 300 µg/kg have been administered subcutaneously to a limited number of healthy volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse events were similar to those in subjects receiving lower doses of pegfilgrastim.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code: L03AA13
Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Pegfilgrastim and filgrastim have been shown to have identical modes of action, causing a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar effects may be seen on some non-myeloid cells in vitro.
In two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancer undergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of pegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence of febrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of 11 daily administrations). In the absence of growth factor support, this regimen has been reported to result in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40% incidence of febrile neutropenia. In one study (n = 157), which used a 6mg fixed dose of pegfilgrastim the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the filgrastim group (difference 0.23 days, 95% CI -0.15, 0.63). Over the entire study, the rate of febrile neutropenia was 13% of pegfilgrastim-treated patients compared with 20% of filgrastim-treated patients (difference 7%, 95% CI of -19%, 5%). In a second study (n = 310), which used a weight-adjusted dose (100 μg /kg), the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 days, 95% CI -0.36, 0.30). The overall rate of febrile neutropenia was 9% of patients treated with pegfilgrastim and 18% of patients treated with filgrastim (difference 9%, 95% CI of -16.8%,-1.1%).
In a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on the incidence of febrile neutropenia was evaluated following administration of a chemotherapy regimen associated with a febrile neutropenia rate of 10-20% (docetaxel 100 mg/m2 every 3 weeks for 4 cycles). Nine hundred and twenty eight patients were randomised to receive either a single dose of pegfilgrastim or placebo approximately 24 hours (Day 2) after chemotherapy in each cycle. The incidence of febrile neutropenia was lower for patients randomised to receive pegfilgrastim compared with placebo (1% versus 17%, p < 0.001). The incidence of hospitalisations and IV anti-infective use associated with a clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group compared with placebo (1% versus 14%, p < 0.001; and 2% versus 10%, p < 0.001).
A small (n = 83), Phase II, randomised, double-blind study in patients receiving chemotherapy for de novo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim, administered during induction chemotherapy. Median time to recovery from severe neutropenia was estimated as 22 days in both treatment groups. Long term outcome was not studied (see section 4.4).
In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients receiving 100 μg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide (VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 x 109) was observed in younger children aged 0-5 yrs (8.9 days) compared to older children aged 6-11 years and 12-21 years (6 days and 3.7 days, respectively) and adults. Additionally a higher incidence of febrile neutropenia was observed in younger children aged 0-5 yrs (75%) compared to older children aged 6-11 years and 12-21 years (70% and 33%, respectively) and adults (see sections 4.8 and 5.2).
5.2 Pharmacokinetic properties
After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during the period of neutropenia after myelosuppressive chemotherapy. The elimination of pegfilgrastim is non-linear with respect to dose; serum clearance of pegfilgrastim decreases with increasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see figure 1).
Figure 1. Profile of Median Pegfilgrastim Serum Concentration and Absolute Neutrophil Count (ANC) in Chemotherapy Treated Patients after a Single 6 mg Injection

Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not expected to be affected by renal or hepatic impairment. In an open label, single dose study (n = 31) various stages of renal impairment, including end-stage renal disease, had no impact on the pharmacokinetics of pegfilgrastim.
Elderly people
Limited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) is similar to that in adults.
Paediatric population
The pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who received 100 μg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest age group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation) (47.9 ± 22.5 μg·hr/ml) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 μg·hr/ml and 29.3 ± 23.2 μg·hr/ml, respectively) (see section 5.1). With the exception of the youngest age group (0-5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients with high-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion of doxorubicin/docetaxel (see sections 4.8 and 5.1).
5.3 Preclinical safety data
Preclinical data from conventional studies of repeated dose toxicity revealed the expected pharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, extramedullary haematopoiesis and splenic enlargement.
There were no adverse effects observed in offspring from pregnant rats given pegfilgrastim subcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity (embryo loss) at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose. In rat studies, it was shown that pegfilgrastim may cross the placenta. Studies in rats indicated that reproductive performance, fertility, oestrous cycling, days between pairing and coitus, and intrauterine survival were unaffected by pegfilgrastim given subcutaneously. The relevance of these findings for humans is not known.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium acetate*
Sorbitol (E420)
Polysorbate 20
Water for injections
*Sodium acetate is formed by titrating glacial acetic acid with sodium hydroxide.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products, particularly with sodium chloride solutions.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Neulasta may be exposed to room temperature (not above 30°C) for a maximum single period of up to 72 hours. Neulasta left at room temperature for more than 72 hours should be discarded.
Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely affect the stability of Neulasta.
Keep the container in the outer carton in order to protect from light.
6.5 Nature and contents of container
Pre-filled syringe (Type I glass), with a rubber stopper and a stainless steel needle with or without an automatic needle guard.
The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex) (see section 4.4).
Each pre-filled syringe contains 0.6 ml of solution for injection. Pack size of one pre-filled syringe, in either a blistered or non-blistered packaging.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Before administration, Neulasta solution should be inspected visually for particulate matter. Only a solution that is clear and colourless should be injected.
Excessive shaking may aggregate pegfilgrastim, rendering it biologically inactive.
Allow the pre-filled syringe to reach room temperature before injecting.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
8. Marketing authorisation number(s)
EU/1/02/227/001 1 pack blistered syringe
EU/1/02/227/002 1 pack unblistered syringe
EU/1/02/227/004 1 pack blistered syringe with needle guard
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 22 August 2002
Date of latest renewal: 16 July 2007
10. Date of revision of the text
May 2015
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu