Neupopeg - summary of medicine characteristics

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.

Excipients:

Excipients known to have a recognised action: sorbitol E420, sodium acet

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless solution for injection.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

One 6 mg dose (a single pre-filled syringe) of Neupopeg is recommended for each chemotherapy cycle, administered as a subcutaneous injection approximately 24 hours following cytotoxic chemotherapy.

Neupopeg is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.

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 Neupopeg 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 Neupopeg 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 Neupopeg administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established.

The safety and efficacy of Neupopeg have not been investigated in patients receiving high dose chemotherapy.

Rare (> 1/10,000 to < 1/1,000) pulmonary adverse effects, 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.

The onset of pulmonary signs such as cough, fever,       spnoea in association with radiological

signs of pulmonary infiltrates, and deterioration in p      ary function along with increased neutrophil

count may be preliminary signs of Adult Respiratory Distress Syndrome (ARDS). In such circumstances Neupopeg should be discontinued at the discretion of the physician and the appropriate treatment given.

Common (> 1/100 to < 1/10) but generally asymptomatic cases of splenomegaly and very rare (< 1/10,000) cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim. 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.

Treatment with Neupopeg 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.

Neupopeg should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.

Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell disease. Therefore, physicians should exercise caution when administering Neupopeg in patients with sickle cell disease, should monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of Neupopeg with splenic enlargement and vaso-occlusive crisis.

White blood cell counts of 100 × 109/l or greater have been observed in less than 1% of patients receiving Neupopeg. 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 Neupopeg.

The safety and efficacy of Neupopeg for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated.

The needle cover 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.

Neupopeg contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Neupopeg contains less than 1 mmol (23 mg) sodium per 6 mg dose, i.e. essentially ‘sodium-free’.

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, Neupopeg should be administered approximately 24 hours after administration of cytotoxic chemotherapy. In clinical studies, Neupopeg has been safely administered 14 days before chemotherapy. Concomitant use of Neupopeg with any chemotherapy agent has not been evaluated in patients. In animal models concomitant administration of Neupopeg 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 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 Neupopeg 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 Neupopeg with any other medicinal products.

4.6 Pregnancy and lactatio

There are no adequate dat from the use of pegfilgrastim in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Neupopeg should not be used during pregnancy unless clearly necessary.

There is no clinical experience with breast-feeding women, therefore Neupopeg should not be administered to women who are breast-feeding.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

In randomised clinical studies in patients with malignancy receiving Neupopeg after cytotoxic chemotherapy, most adverse events were caused by the underlying malignancy or cytotoxic chemotherapy.

The most frequently reported and very common study-drug related undesirable effect was bone pain Bone pain was generally of mild-to-moderate severity, transient and could be controlled in most patients with standard analgesics.

Allergic-type reactions, including anaphylaxis, skin rash, urticaria, angioedema, dyspnoea, hypotension, injection site reactions, erythaema and flushing, occurring on initial or subsequent treatment have been reported with Neupopeg. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Pegfilgrastim should be permanently discontinued in patients who experience a serious allergic reaction.

Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical effects, were common (> 1/100 to < 1/10); reversible, mild to moderate elevations in lactate dehydrogenase, with no associated clinical effects, were very common (> 1/10) in patients receiving Neupopeg following cytotoxic chemotherapy. Nausea was observed in healthy volunteers and patients receiving chemotherapy.

Common (> 1/100 to <1/10) but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim (see section 4.4). Other commonly reported undesirable effects include pain, injection site pain; chest pain (non-cardiac); headache; arthralgia; myalgia; back, limb, musculo-skeletal and neck pain.

Rare (> 1/10,000 to < 1/1,000) pulmonary adverse effects including interstitial pneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. Some of the reported cases have resulted in respiratory failure or Adult Respiratory Distress Syndrome (ARDS), which may be fatal (see section 4.4)

Rare (> 1/10,000 to < 1/1,000) cases of thrombocytopenia

Rare (> 1/10,000 to < 1/1,000) cases of Sweet’s syndrome have been reported, although in some cases underlying haematological malignancies may play a role.

Very rare (< 1/10,000) events of cutaneous vasculitis have been reported in patients treated with Neupopeg. The mechanism of vasculitis in patients receiving Neupopeg is unknown.

Very rare (< 1/10,000) elevations in liver function tests (LFTs) for ALT (alanine aminotransfera

Isolated cases of sickle cell crises have been reported in patients with sickle cell disease (see section 4.4).

4.9 Overdose

There is no experience with overdose of Neupopeg in humans.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cytokines, 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 microgram­s/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 r pegfilgrastim or placebo approximately 24 hours (Day 2) 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).

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).

5.3 Preclinical safety data

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Neupopeg may be exposed to room temperature (not above 30°C) for a maximum single period of up to 72 hours. Neupopeg 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 Neupopeg.

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

6.5 Nature and contents of container

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) (see section 4.4).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other h

Before administration, Neupopeg 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.

Dompé Biotec S.p.A Via San Martino 12 I-20122 Milan

Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/228/001–002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 August 2002

Date of last renewal: 16 July 2007

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency (EMEA)