Recombinant human glycosylated G- CSF.

Lenograstim

GRANOCYTE 13 million IU/mL, powder and solvent for solution for injection/infusion. GRANOCYTE 13 million IU/mL, powder and solvent for solution for injection/infusion in a pre-filled syringe. GRANOCYTE 34 million IU/mL, powder and solvent for solution for injection/infusion. GRANOCYTE 34 million IU/mL, powder and solvent for solution for injection/infusion in a pre-filled syringe.

Powder and solvent for solution for injection/infusion. 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.

• 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 13 million IU/mL can be used in patients with body surface area up to 0.7 m².

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.

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%.

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

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

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.

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.

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.

Data on long-term follow-up of donors are available on a small number of subjects. Up to six years, no emerging long-term sequelae have been reported. Nevertheless, a risk of promotion of a malignant myeloid clone is possible. Therefore, it is recommended that systematic recording and tracking of the stem-cell gifts be made by the apheresis centres.

• 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.

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

• 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.

• 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.

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

Chugai Pharma UK Limited

(POM)

26 June 2009