GRANOCYTE 34 million IU/mL, powder and solvent for solution for injection/infusion in a pre-filled syringe.

Lenograstim* (rHuG-CSF) 33.6 million International Units (equivalent to 263 micrograms) per mL after reconstitution

*Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells.

Excipients known to have a recognised action or effect: phenylalanine

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection/infusion in a pre-filled syringe.

− White powder

− Solvent: clear, colourless solution

• Reduction in the duration of neutropenia in patients (with non myeloid malignancy) undergoing myeloablative therapy followed by bone marrow transplantation (BMT) in patients considered to be at increased risk of prolonged severe neutropenia.

• Reduction of duration of severe neutropenia and its associated complications in patients undergoing established cytotoxic chemotherapy associated with a significant incidence of febrile neutropenia.

• Mobilisation of peripheral blood progenitor cells (PBPCs).

Therapy should only be given in collaboration with an experienced oncology and/or haematology centre.

GRANOCYTE can be administered by sub-cutaneous injection or by intravenous infusion. Particular handling of the product or instructions for preparation are given in sections 6.6.

• The recommended dose of GRANOCYTE is 150 µg (19.2 MIU) per m² per day, therapeutically equivalent to 5 µg (0.64 MIU) per kg per day for:

• Peripheral Stem Cells or bone marrow transplantation,

• established cytotoxic chemotherapy

• PBPC mobilisation after chemotherapy.

GRANOCYTE 34 million IU/mL can be used in patients with body surface area up to 1.8 m².

For PBPC mobilisation with GRANOCYTE alone, the recommended dose is 10 µg (1.28 MIU) per kg per day.

4.2.1 Adults

• In Peripheral Stem Cells or Bone Marrow Transplantation

GRANOCYTE should be administered daily at the recommended dose of 150 µg (19.2 MIU) per m² per day as a 30-minute intravenous infusion diluted in isotonic saline solution or as a subcutaneous injection. The first dose should not be administered within 24 hours of the bone marrow infusion. Dosing should continue until the expected nadir has passed and the neutrophil count returns to a stable level compatible with treatment discontinuation, with, if necessary, a maximum of 28 consecutive days of treatment.

It is anticipated that by day 14 following bone marrow transplantation, 50% of patients will achieve neutrophil recovery.

• In Established Cytotoxic Chemotherapy

GRANOCYTE should be administered daily at the recommended dose of 150 µg (19.2 MIU) per m² per day as a subcutaneous injection. The first dose should not be administered less than 24 hours following cytotoxic chemotherapy (see 4.4 and 4.5). Daily administration of GRANOCYTE should continue until the expected nadir has passed and the neutrophil count returns to a stable level compatible with treatment discontinuation, with, if necessary, a maximum of 28 consecutive days of treatment.

A transient increase in neutrophil count may occur within the first 2 days of treatment, however GRANOCYTE treatment should not be stopped, since the subsequent nadir usually occurs earlier and recovers more quickly if treatment continues.

• In Peripheral Blood Progenitor Cells (PBPCs) Mobilisation

After chemotherapy, GRANOCYTE should be administered daily, at the recommended dose of 150 µg (19.2 MIU) per m² per day as a subcutaneous injection starting within 1 to 5 days after completion of chemotherapy, according to the chemotherapy regimen administered for mobilisation.

Granocyte should be maintained until the last leukapheresis.

Leukapheresis should be performed when the post nadir leukocyte count is rising or after assessment of CD34⁺ cells in blood with a validated method. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient to obtain the acceptable minimum yield ( 2.0 x 10⁶ CD34⁺ cells per kg).

In PBPC mobilisation with GRANOCYTE alone, GRANOCYTE should be administered daily at the recommended dose of 10 µg (1.28 MIU) per kg per day as a subcutaneous injection for 4 to 6 days. Leukapheresis should be performed between day 5 and 7.

In patients who have not had extensive chemotherapy one leukapheresis is often sufficient to obtain the acceptable minimum yield ( 2.0 x 10⁶ CD34⁺ cells per kg).

In healthy donors, a 10µg/kg daily dose administered subcutaneously for 5-6 days allows a CD34⁺ cells collection 3 x 10⁶ /kg body weight with a single leukapheresis in 83% of subjects and with 2 leukapheresis in 97%.

4.2.2 Elderly

Clinical trials with GRANOCYTE have included a small number of patients up to the age of 70 years but special studies have not been performed in the elderly and therefore specific dosage recommendations cannot be made.

4.2.3 Children

The safety and efficacy of GRANOCYTE have been established in patients older than 2 years in BMT.

GRANOCYTE should not be administered to patients with known hypersensitivity to lenograstim or to any of the excipients.

GRANOCYTE should not be used to increase the dose intensity of cytotoxic chemotherapy beyond established doses and dosage regimens since the drug could reduce myelo-toxicity but not overall toxicity of cytotoxic drugs.

It should not be administered concurrently with cytotoxic chemotherapy.

It should not be administered to patients

• with myeloid malignancy other than de novo acute myeloid leukaemia,

• with de novo acute myeloid leukaemia aged below 55 years,

• and/or with de novo acute myeloid leukaemia with good cytogenetics, i.e. t(8 ;21), t(15 ;17) and inv (16).

• Malignant Cell Growth

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 GRANOCYTE administration in patients with myelodysplasia or secondary AML or chronic myelogenous leukaemia have not been established. Therefore, it should not be used in these indications. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.

Clinical trials have not established whether GRANOCYTE influences the progression of myelodysplastic syndrome to acute myeloid leukaemia. Caution should be exercised in using it in any pre-malignant myeloid condition. As some tumours with non-specific characteristics can exceptionally express a G-CSF receptor, caution should be exerted in the event of unexpected tumour regrowth concomitantly observed with rHuG-CSF therapy

• Leukocytosis

A leukocyte count greater than 50 x 10⁹/L has not been observed in any of the 174 clinical trials patients treated with 5 µg/kg/day (0.64 million units/kg/day) following bone marrow transplantation. White blood cell counts of 70 x 10⁹/L or greater have been observed in less than 5% of patients who received cytotoxic chemotherapy and were treated by GRANOCYTE at 5 µg/kg/day (0.64 million units/kg/day). No adverse events directly attributable to this degree of leukocytosis have been reported. In view of the potential risks associated with severe leukocytosis, a white blood cell count should, however, be performed at regular intervals during GRANOCYTE therapy.

If leukocyte counts exceed 50 x 10⁹/L after the expected nadir, GRANOCYTE should be discontinued immediately.

During PBPC mobilisation, GRANOCYTE should be discontinued if the leukocyte counts rise to > 70 x 10⁹/L.

• Pulmonary adverse effects

Rare (>0.01% and <0.1%) pulmonary adverse effects, in particular interstitial pneumonia, have been reported after G-CSFs administration.

Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk.

The onset of pulmonary symptoms or signs, such as cough, fever and dyspnoea, in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute respiratory distress syndrome (ARDS).

GRANOCYTE should be immediately discontinued and appropriate treatment given.

• In Peripheral Stem Cells or Bone Marrow Transplantation

Special attention should be paid to platelet recovery since in double-blind placebo-controlled trials the mean platelet count was lower in patients treated with GRANOCYTE as compared with placebo.

The effect of GRANOCYTE on the incidence and severity of acute and chronic graft-versus-host disease has not been accurately determined.

• In Established Cytotoxic Chemotherapy

The use of GRANOCYTE is not recommended from 24 hours before, until 24 hours after chemotherapy ends (see section 4.5).

The safety of the use of GRANOCYTE with antineoplastic agents characterized by cumulative or predominant platelet lineage myelotoxicity (nitrosurea, mitomycin) has not been established. Administration of GRANOCYTE might enhance the toxicity of these agents, particularly to the platelets.

• Risks Associated with Increased Doses of Chemotherapy

The safety and efficacy of GRANOCYTE have yet to be established in the context of intensified chemotherapy. It should not be used to decrease, beyond the established limits, intervals between chemotherapy courses and/or to increase the doses of chemotherapy. Non-myeloid toxicities were limiting factors in a phase II chemotherapy intensification trial with GRANOCYTE.

• Special precautions in Peripheral Blood Progenitor Cells mobilisation.

Choice of the mobilisation method

Clinical trials carried out among the same patient population have shown that PBPC mobilisation, as assessed within the same laboratory, was higher when GRANOCYTE was used after chemotherapy than when used alone. Nevertheless the choice between the two mobilisation methods should be considered in relation to the overall objectives of treatment for an individual patient.

Prior exposure to radiotherapy and/or cytotoxic agents

Patients, who have undergone extensive prior myelosuppressive therapy and/or radiotherapy, may not show sufficient PBPC mobilisation to achieve the acceptable minimum yield ( 2 x10⁶ CD34⁺ /kg) and therefore adequate haematological reconstitution.

A PBPC transplantation program should be defined early in the treatment course of the patient and particular attention should be paid to the number of PBPC mobilised before the administration of high-dose chemotherapy. If yields are low, other forms of treatment should replace the PBPC transplantation program.

Assessment of progenitor cell yields

Particular attention should be paid to the method of quantification of progenitor cell yields as the results of flow cytometric analysis of CD34⁺ cell number vary among laboratories.

The minimum yield of CD34⁺ cells is not well defined. The recommendation of a minimum yield of 2.0 x 10⁶ CD34+ cells/kg is based on published experience in order to achieve adequate haematological reconstitution. Yields higher than 2.0 x 10⁶ CD34⁺ cells/kg are associated with more rapid recovery, including platelets, while lower yields result in slower recovery.

• In healthy donors

The PBPC mobilisation, which is a procedure without direct benefit for healthy people, should only be considered through a clear regular delimitation in accordance with local regulations as for bone marrow donation when applicable.

The efficacy and safety of GRANOCYTE has not been assessed in donors aged over 60 years, therefore the procedure cannot be recommended. Based on some local regulations and lack of studies, minor donors should not be considered.

PBPC mobilisation procedure should be considered for donors who fit usual clinical and laboratory eligibility criteria for bone marrow donation especially normal haematological values.

Marked leukocytosis (WBC 50 x 10⁹/L) was observed in 24% of subjects studied.

Apheresis-related thrombocytopenia (platelets < 100 x 10⁹/L) was observed in 42% of subjects studied and values < 50 x 10⁹/L were occasionally noted following leukapheresis without related clinical adverse events, all recovered. Therefore leukapheresis should not be performed in donors who are anticoagulated or who have known defects in haemostasis. If more than one leukapheresis is required particular attention should be paid to donors with platelets < 100 x 10⁹/L prior to apheresis ; in general apheresis should not be performed if platelets < 75 x 10⁹/L.

Insertion of a central venous catheter should be avoided if possible with consideration given to venous access in selection of donors.

Transient cytogenetic modifications have been observed in normal donors following G-CSF use. The significance of these changes is unknown.

Long-term safety follow up of donors is ongoing. Nevertheless, a risk of promotion of a malignant myeloid clone cannot be excluded. It is recommended that the apheresis centre perform a systematic record and tracking of the stem cell donors for at least 10 years to ensure monitoring of long-term safety.

In normal donors, pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, dyspnoea and hypoxia) have been reported in post marketing experience. In case of suspected or confirmed pulmonary adverse events, discontinuation of treatment with Granocyte should be considered and appropriate medical care given.

• In recipients of allogeneic peripheral stem-cells mobilised with GRANOCYTE

Allogeneic stem-cell grafting may be associated with an increased risk for chronic GVH (Graft Versus Host Disease), and long-term data of graft functioning are sparse.

• Other Special Precautions

In patients with severe impairment of hepatic or renal function, the safety and efficacy of GRANOCYTE have not been established.

In patients with substantially reduced myeloid progenitor cells (e.g. due to prior intensive radiotherapy/chemotherapy), neutrophil response is sometimes diminished and the safety of GRANOCYTE has not been established.

Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been reported in either healthy donors or patients following administration of Granulocyte-colony stimulating factors (G-CSFs). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered when left upper abdominal pain or shoulder tip pain is reported.

GRANOCYTE contains phenylalanine, which may be harmful for people with phenylketonuria.

In view of the sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, the use of GRANOCYTE is not recommended from 24 hours before until 24 hours after chemotherapy ends (see section 4.4).

Possible interactions with other haematopoietic growth factors and cytokines have yet to be investigated in clinical trials.

• Pregnancy

There are no adequate data from the use of lenograstim in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

GRANOCYTE should not be used during pregnancy unless clearly necessary.

• Lactation

It is unknown whether lenograstim is excreted in human milk. The excretion of lenograstim in milk has not been studied in animals. Breast-feeding should be discontinued during therapy with GRANOCYTE.

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

• In Peripheral Stem Cells or Bone Marrow Transplantation

In double-blind placebo-controlled trials the mean platelet count was lower in patients treated with GRANOCYTE as compared with placebo without an increase in incidence of adverse events related to blood loss and the median number of days following BMT to last platelet infusion was similar in both groups (see section 4.4).

• In Peripheral Stem Cells or Bone Marrow Transplantation and Chemotherapy-Induced Neutropenia

In clinical trials, the most frequently reported adverse events (15%) were the same in patients treated with either GRANOCYTE or placebo. These adverse events were those usually encountered with conditioning regimens and those observed in cancer patients treated with chemotherapy. The most commonly reported adverse events were infection/inflammatory disorder of the buccal cavity, sepsis and infection, fever, diarrhoea, abdominal pain, vomiting, nausea, rash, alopecia, and headache.

• In PBPC mobilisation in healthy donors

The most frequently reported undesirable effects were transient and mild to moderate: pain, bone pain, back pain, asthenia, fever, headache and nausea, increased ALAT, ASAT, blood alkaline phosphatise and LDH.

Apheresis-related thrombocytopenia and leukocytosis were observed in 42% and 24% respectively in study subjects.

Common but generally asymptomatic cases of splenomegaly and very rare cases of splenic rupture have been reported.

Rare pulmonary adverse reactions have been reported like dyspnoea, hypoxia or haemoptysis, including very rarely Acute Respiratory Distress Syndrome (ARDS) (see section 4.4).

Allergic reactions including anaphylaxis have been reported very rarely after the first subcutaneous administration of lenograstim.

Frequency of adverse reactions issued from clinical trials and post-marketing surveillance data. Very common ( 10%); common ( 1/100 to < 1/10); uncommon ( 1/1000 to 1/100); rare ( 1/10000 to 1/1000); very rare ( 1/10000); not known (cannot be estimated from the available data).

1 / The risk of occurrence of pain is increased in subjects with high peak WBC values, especially when WBC 50 x 10⁹/L

2 / Transient increase of ASAT and/or ALAT was observed. In most cases, liver function abnormalities improved after lenograstim discontinuation.

3 / Some of the respiratory reported cases have resulted in respiratory failure or acute respiratory distress syndrome (ADRS) which may be fatal.

4 / Sweet's syndrome, erythema nodosum and pyoderma gangrenosum were mainly described in patients with hematological malignancies, a condition known to be associated with neutrophilic dermatosis, but also in non-malignant related neutropenia.

5 / Splenic ruptures have been reported in either healthy donors or patients receiving G-CSFs (see section 4.4)

The effects of GRANOCYTE overdose have not been established (see section 5.3). Discontinuation of GRANOCYTE 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. A white blood cell count of approximately 50 x 10⁹/L was observed in one patient out of three receiving the highest GRANOCYTE dose of 40 µg/kg/day (5.12 MIU/kg/day) on the 5th day of treatment. In humans, doses up to 40 µg/kg/day were not associated with toxic side effects except musculoskeletal pain.

Pharmacotherapeutic group: Cytokines, ATC code: L03AA10

Lenograstim (rHuG-CSF) belongs to the cytokine group of biologically active proteins which regulate cell differentiation and cell growth.

rHuG-CSF is a factor that stimulates neutrophil precursor cells as demonstrated by the CFU-S and CFU-GM cell count which increases in peripheral blood.

GRANOCYTE induces a marked increase in peripheral blood neutrophil counts within 24 hours of administration.

Elevations of neutrophil count are dose-dependent over the 1-10 µg/kg/day range. At the recommended dose, repeated doses induce an enhancement of the neutrophil response. Neutrophils produced in response to GRANOCYTE show normal chemotactic and phagocytic functions.

As with other hematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.

Use of GRANOCYTE in patients who underwent Bone Marrow Transplantation or who are treated with cytotoxic chemotherapy leads to significant reductions in duration of neutropenia and its associated complications.

Use of GRANOCYTE either alone or after chemotherapy mobilises haematopoietic progenitor cells into the peripheral blood. These autologous Peripheral Blood Progenitor Cells (PBPCs) can be harvested and infused after high dose cytotoxic chemotherapy, either in place of, or in addition to bone marrow transplantation.

Reinfused PBPCs, as obtained following mobilisation with GRANOCYTE have been shown to reconstitute haemopoiesis and reduce the time to engraftment, leading to a marked decrease of the days to platelets independence when compared to autologous bone marrow transplantation.

A pooled analysis of data from 3 double-blind placebo-controlled studies conducted in 861 patients (n=411 55 years) demonstrated a favourable benefit/risk ratio of lenograstim administration in patients over 55 years of age undergoing conventional chemotherapy for de novo acute myeloid leukaemia, in the exception of AML with good cytogenetics, i.e. t(8 ;21), t(15 ;17) and inv (16).

The benefit in the sub-group of patients over 55 years appeared in terms of lenograstim-induced acceleration of neutrophil recovery, increase in the percentage of patients without infectious episode, reduction in infection duration, reduction in the duration of hospitalisation, reduction in the duration of IV antibiotherapy. However, these beneficial results were not associated with decreased severe or life-threatening infections incidence, nor with decreased infection-related mortality.

Data from a double-blind placebo-controlled study conducted in 446 patients with de novo AML showed that, in the 99 patients subgroup with good cytogenetics, the event-free survival was significantly lower in the lenograstim arm than in the placebo arm, and there was a trend towards a lower overall survival in the lenograstim arm when compared to data from the not good cytogenetics subgroup.

The pharmacokinetics of GRANOCYTE are dose and time dependent.

During repeated dosing (IV and SC routes), peak serum concentration (immediately after IV infusion or after SC injection) is proportional to the injected dose. Repeated dosing with GRANOCYTE by the two administration routes showed no evidence of drug accumulation.

At the recommended dose, the absolute bioavailability of GRANOCYTE is 30%. The apparent volume of distribution (Vd) is approximately 1 L/kg body weight and the mean residence time close to 7 h following subcutaneous dosing.

The apparent serum elimination half-life of GRANOCYTE (S.C. route) is about 3-4 h, at steady state (repeated dosing) and is shorter (1-1.5 h) following repeated IV infusion.

Plasma clearance of rHuG-CSF increased 3-fold (from 50 up to 150 mL/min) during repeated S.C. dosing. Less than 1% of lenograstim is excreted in urine unchanged and it is considered to be metabolised to peptides. During multiple S.C. dosing, peak serum concentrations of lenograstim are close to 100 pg/mL/kg body weight at the recommended dosage. There is a positive correlation between the dose and the serum concentration of GRANOCYTE and between the neutrophil response and the total amount of lenograstim recovered in serum.

In animals, acute toxicity studies (up to 1000 µg/kg/day in mice) and sub-acute toxicity studies (up to 100 µg/kg/day in monkey) showed the effects of overdose were restricted to an exaggerated and reversible pharmacological effect.

There is no evidence from studies in rats and rabbits that GRANOCYTE is teratogenic. An increased incidence of embryo-loss has been observed in rabbits, but no malformation has been seen.

Powder

Arginine

Phenylalanine

Methionine

Mannitol (E421)

Polysorbate 20

Diluted hydrochloric acid (for pH adjustment)

Solvent

Water for injections

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

2 years.

After reconstitution or dilution, an immediate use is recommended. However, in-use stability of the reconstituted/diluted medicinal product has been demonstrated for 24 hours at 2°C - 8°C (in a refrigerator)

Do not store above + 30°C.

Do not freeze.

For storage conditions of the reconstituted/diluted medicinal product, see section 6.3.

263 micrograms of powder in vial (type I glass) with a rubber stopper (type I butyl rubber) + 1 mL of solvent in pre-filled syringe (type I glass) + 2 needles (19G and 26 G); pack size of 1 or 5.

Not all pack sizes may be marketed.

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

In view of the possible risk of microbial contamination, pre-filled syringe with solvent is for single use only.

Instructions for preparation

GRANOCYTE vials are for single-dose use only.

GRANOCYTE must be reconstituted before sub-cutaneous or intravenous administration.

Preparation of the reconstituted GRANOCYTE solution

Using the 19G needle provided in the pack, and the pre-filled disposable syringe with the solvent for GRANOCYTE ready for immediate use aseptically add the extractable contents of one pre-filled syringe of solvent for GRANOCYTE to the GRANOCYTE vial.

Agitate gently until completely dissolved. Do not shake vigorously.

The reconstituted parenteral solution appears transparent and free of particles.

The reconstituted solution should preferably be used immediately after preparation. For storage conditions of the reconstituted/diluted medicinal product, see section 6.3.

Preparation for the subcutaneous administration

Prepare a reconstituted GRANOCYTE solution as described above.

Keeping the needle 19G and the syringe attached to the vial , withdraw the required volume of reconstituted solution from the vial. Replace the needle used for reconstitution and fit the syringe with the 26G needle provided for subcutaneous injection.

Administer immediately by sub-cutaneous injection (refer to section 4.2 for administration requirements).

Preparation of the infusion solution for the intravenous administration:

When intravenous use GRANOCYTE has to be diluted after reconstitution.

Prepare a reconstituted GRANOCYTE solution as described above.

Keeping the needle and the syringe attached to the vial, withdraw the required volume of reconstituted solution from the vial.

Dilute the reconstituted GRANOCYTE solution to the required concentration by injecting the required volume into either 0.9% sodium chloride or 5% dextrose solution.

Administer by IV route (refer to section 4.2 for administration requirements)

GRANOCYTE is compatible with the commonly used administration sets for injection when diluted either in a 0.9% saline solution (polyvinyl chloride bags and glass bottles) or in a 5% dextrose solution (glass bottles)

Dilution of GRANOCYTE 34 million IU/mL to a final concentration of less than 0.32 million IU/mL (2.5 µg/mL) is not recommended. 1 vial of reconstituted GRANOCYTE 34 million IU/mL should not be diluted in more than 100 mL.

Chugai Pharma UK Ltd

Mulliner House

Flanders Road

Turnham Green

London.

W4 1NN

PA 0950/002/001

Date of first authorisation: 25 July 1996

Date of last renewal: 28 July 2008

April 2011