4.1. Therapeutic indications

GRANOCYTE is indicated in adults, adolescents and children aged older than 2 years for:

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

▪ The reduction of the duration of severe neutropenia and its associated complications in patients undergoing established cytotoxic therapy associated with a significant incidence of febrile neutropenia.

▪ The mobilisation of peripheral blood progenitor cells (PBPCs), for patients as well as healthy donors.

4.2. Posology and method of administration

Method of administration

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.

Posology

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

The recommended dose of GRANOCYTE is 19.2 MIU (150 µg) per m2 per day, therapeutically equivalent to 0.64 MIU (5 µg) 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 1.28 MIU (10 µg) per kg per day.

Adults

▪ In Peripheral Stem Cells or Bone Marrow Transplantation

GRANOCYTE should be administered daily at the recommended dose of 19.2 MIU (150 µg) 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 19.2 MIU (150 µg) () 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 19.2 MIU (150 µg) 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 1.28 MIU (10 µg) 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%.

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.

Paediatric Population

The dose in children older than 2 years and adolescent is the same as in adults when used to reduce the duration of neutropenia after myeloablative therapy followed by BMT or after cytotoxic chemotherapy.

Very limited data are available for mobilisation of peripheral blood progenitor cells at the adult dose.

The safety and efficacy of GRANOCYTE in children aged less than 2 years have not been established.

GRANOCYTE 13 million IU/mL may be the more appropriate dosage for administration in children 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.

4.3. Contraindications

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

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).

4.4. Special warnings and precautions for use

▪ 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

▪ In children with ALL

An increased risk for secondary myeloid leukaemia or myelodysplastic syndrome associated with CSFs has been reported in children with ALL. A comparable risk has been established by a systematic review of 25 randomized controlled trials in 12.804 adult patients with solid tumors or lymphomas, a risk, however, without negative impact on long term outcome in the adults investigated. Therefore, GRANOCYTE 13 million IU/mL and GRANOCYTE 34 million IU/ml should be used in children, in particular with favorable long term prognosis, only after careful weighting of short term benefits versus long term risks.

▪ 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 donors and patients, 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.

▪ Venous and arterial thromboembolic events

Cases of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (such as myocardial infarction and cerebrovascular event) have been reported in donors treated with lenograstim. Close monitoring is recommended in donors and patients with known risk factors for thrombosis (see section 4.8).

▪ 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 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) including lenograstim (see section 4.8). Therefore, spleen size should be carefully monitored (e.g. clinical examination, ultrasound). If enlargement of the spleen is observed during lenograstim therapy, appropriate therapeutic measures should be taken including discontinuing administration of the product. A diagnosis of splenic rupture should be considered when left upper abdominal pain or shoulder tip pain is reported.

Capillary leak syndrome has been reported after G-CSF administration, and is characterised by hypotension, hypoalbuminaemia, oedema and hemoconcentration. Lenograstim should be discontinued if patients develop symptoms of capillary leak syndrome, and appropriate symptomatic treatment, which may include a need for intensive care, should be given (see section 4.8).

Sickle cell crisis may be potentially associated with the use of lenograstim in patients with sickle cell trait or sickle cell disease. Therefore, physicians should use caution when prescribing Granocyte in patients with sickle cell trait or sickle cell disease.

Glomerulonephritis has been reported in patients and donors receiving lenograstim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of G-CSF. Urinalysis monitoring is recommended.

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

Aortitis has been reported after G-CSF administration in healthy donors and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8.

Traceability:

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

Breast-feeding

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.

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

The safety profile in children, adolescents, and adults is comparable.

▪ 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.

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

• Post-marketing life-threatening Adverse Drug Reaction (ADR)

Capillary leak syndrome which can be life-threatening if treatment is delayed has been reported uncommonly (≥ 1/1000 to < 1/100) in the post-marketing setting following administration of granulocyte-colony-stimulating factors, mostly in cancer patients undergoing chemotherapy (see section 4.4).

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).

Medra System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Not known

Investigations

Elevated LDH

C-reactive protein increased

Blood and lymphatic system disorders

Leucocytosis

Thrombocytopenia

Enlarged spleen size

Splenic rupture (5)

Nervous system disorders

Headache

Asthenia

Vascular Disorders

Capillary leak syndrome6

Aortitis

Venous thromboembolism

Arterial thromboembolism

Respiratory, thoracic and mediastinal disorders

Haemoptysis (8)

Pulmonary edema

Interstitial pneumonia (3)

Pulmonary infiltrates

Pulmonary fibrosis

Pulmonary haemorrhage (8)

Gastrointestinal disorders

Abdominal pain

Skin and subcutaneous tissue disorders

Cutaneous vasculitis

Sweet's syndrome (4)

Erythema nodosum

Pyoderma gangrenosum

Lyell's syndrome

Musculoskeletal and connective tissue disorders

Musculoskeletal pain (7)

Pain (1)

Renal and urinary disorders

Glomerulonephritis

General disorders and administration site condition

Injection site reaction

Immune system disorders

Allergic reaction

Anaphylactic shock

Hepatobiliary disorders

Elevated ASAT/ALAT (2)

Elevated Alkaline-phosphatase

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 (ARDS) 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)

6 / There have been post-marketing reports of life-threatening capillary leak syndrome (see section 4.4)

7 / includes bone pain, back pain, arthralgia, myalgia and pain in extremity

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

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 the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).

4.9. Overdose

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.