Consumer medicine information

Granocyte

Lenograstim

BRAND INFORMATION

Brand name

Granocyte

Active ingredient

Lenograstim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Granocyte.

What is in this leaflet

This leaflet answers some common questions about GRANOCYTE. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given GRANOCYTE against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What GRANOCYTE is used for

GRANOCYTE is a synthetic (man-made) version of a substance called granulocyte colony-stimulating factor (G-CSF) which is produced naturally by the human body.

G-CSF is produced by certain cells within the bone marrow to stimulate the production of neutrophils (a type of white blood cell). Neutrophils help the body to prevent or fight infection. A low neutrophil level increases your risk of infection. GRANOCYTE is therefore used to (help) increase the neutrophil count in those with low white blood cell counts, a condition known as neutropenia.

A low number of neutrophils in your blood (neutrophil count) often occurs after bone marrow transplantation or chemotherapy. On rare occasions, infants have a low neutrophil count present at birth (congenital neutropenia).

Stem Cell Transplantation
Some chemotherapy drugs have toxic effects on the bone marrow. Your doctor may collect stem cells (the parent cells of all blood cells) from your blood before you have chemotherapy.

There are normally only a small number of stem cells in the blood. GRANOCYTE can be used to increase the number of stem cells in the blood. The stem cells are then collected by a procedure, called leukapheresis, done in hospital.

The stem cells collected from the blood are stored until after you have had your chemotherapy. They are then given back to you to replace those cells destroyed by the chemotherapy drugs. This is known as a stem cell transplantation. You may also be given GRANOCYTE after your stem cell transplantation to help speed up your recovery.

GRANOCYTE can also be used in healthy donors in order to collect their stem cells for transplantation into patients.

Bone Marrow Transplantation
Bone marrow transplantation is a procedure used to treat certain types of cancers, especially those that originate in the bone marrow (leukaemia). It involves destroying your bone marrow with chemotherapy and/or radiotherapy and replacing it with a bone marrow graft either from yourself or a donor. The neutrophil count will fall to a very low level soon after you receive your transplant.

GRANOCYTE is used after bone marrow transplantation to speed up the increase in your neutrophil count to reduce your risk of developing an infection.

Chemotherapy
Chemotherapy is used to destroy cancer cells. Sometimes chemotherapy also destroys other cells, such as neutrophils. This may increase your risk of infection.

GRANOCYTE is used after chemotherapy to increase the neutrophil count. This will reduce the likelihood of infection.

Congenital Neutropenia
Children born with low neutrophil count suffer frequently from infections. This is called congenital neutropenia. On occasions, the infection may be severe, requiring hospitalisation and intravenous antibiotics.

GRANOCYTE is used in patients with congenital neutropenia to raise and maintain the neutrophil count and hence reduce the likelihood of infection.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor’s prescription.

Before you are given GRANOCYTE

When you must not be given it

You must not be given GRANOCYTE if you have an allergy to:

  • any medicine containing lenograstim
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given this medicine if you have any of the following medical conditions:

  • myelodysplasia (an abnormality of bone marrow cells),
  • acute myeloid leukaemia (AML) (a cancer of bone marrow cells), or
  • chronic myeloid leukaemia (CML) (a cancer of bone marrow cells).

There is a possibility that GRANOCYTE may promote the growth of these abnormal cells. If you have any concerns about this, talk to your doctor.

You must not be given GRANOCYTE if you are currently receiving chemotherapy medicines. GRANOCYTE is normally started on the day after chemotherapy is finished; or on the day after your bone marrow transplant or stem cell transplant.

You must not be given GRANOCYTE if you are a healthy donor and you are over 60 years of age or under 18 years of age. The safety and effectiveness of GRANOCYTE in healthy donors in these age groups have not been studied.

Do not use GRANOCYTE if the vial has been used before. GRANOCYTE vials are intended for single-use only. They do not contain a preservative and there is a possibility of contamination with repeated use. Any unused GRANOCYTE should be discarded.

Do not use GRANOCYTE if you have prepared the solution and it has not been stored in a refrigerator. As GRANOCYTE does not contain a preservative, there is a risk that any prepared solution that has not been stored in a refrigerator may be contaminated with germs and cause an infection.

Do not use if you have prepared the solution of GRANOCYTE more than 24 hours ago (even if stored in a refrigerator).

Do not use if the solution of GRANOCYTE is not clear and colourless, or it contains particles.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering, or if the vial cap shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have any of the following medical conditions:

  • kidney disease, or are undergoing dialysis
  • liver disease
  • sickle cell disease or a similar blood disease

Tell your doctor if you have recently:

  • had pneumonia (or other serious lung infections).

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved. It is not known whether GRANOCYTE is excreted in human milk.

If you have not told your doctor about any of the above, tell him/her before you are given GRANOCYTE.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and GRANOCYTE may interfere with each other. These include:

  • medicines used to treat cancer (cytotoxic chemotherapy).

These medicines may be affected by GRANOCYTE or may affect how well it works. It is recommended that GRANOCYTE should start on the day following completion of chemotherapy.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while being treated with this medicine.

Driving and using machinery

The effect of GRANOCYTE on the ability to drive or use machines or tools is not known. Wait to see how GRANOCYTE affects you before driving or using tools or machines.

How GRANOCYTE is given

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How much is given

Your doctor will decide what dose you will receive. This will depend on your condition, your body weight and the number of white blood cells (neutrophils) in your blood.

How it is given

Dissolve each vial of GRANOCYTE with 1.0mL sterile Water for Injections before use.

GRANOCYTE is given as an injection into a vein or an injection under the skin.

GRANOCYTE may be given to you by a doctor or nurse while you are a hospital in-patient, or attending an out-patient clinic. Alternatively, you may be able to receive injections of GRANOCYTE at home. In such cases, you or your carer will be taught how to inject GRANOCYTE under the skin (subcutaneously). Be sure to inject the exact dose that your doctor has prescribed.

If you will be self-administering GRANOCYTE your doctor or nurse will provide you with proper training and instruction on how to prepare your injection, and where and how to do the injection.

How long it is given

Your doctor will tell you how many days you will need to receive treatment with GRANOCYTE.

Continue treatment with your medicine for as long as your doctor tells you. It is important that you continue to receive your medicine even if you feel well.

The duration of use varies according to your condition:

  • if you are having a bone marrow transplant or stem cell transplant, usually only one course of GRANOCYTE is required
  • if you are a healthy donor of stem cells, usually only one course of GRANOCYTE is required (with a maximum of 28 consecutive days of treatment)
  • if you are having chemotherapy, your doctor may prescribe several courses of treatment with GRANOCYTE
  • if you have congenital neutropenia, your doctor may prescribe continuous or intermittent treatment with GRANOCYTE.

If you forget to have your injection

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you receive too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have been given too much GRANOCYTE. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Ask your doctor or pharmacist if you have any concerns.

While you are being given GRANOCYTE

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given GRANOCYTE.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given this medicine.

If you become pregnant while you are being treated with this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are being given this medicine. It may interfere with the results of some tests.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor will do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Measure your temperature every day, and be alert for other signs of an infection. Do this before your injection of GRANOCYTE. You should watch for fever - a temperature of 38.2°C or greater, or as your doctor suggests. Your body’s ability to fight infection is reduced and it is therefore very important that you look for signs or symptoms of infection. Signs or symptoms of infection include:

  • fever
  • chills
  • shaking
  • sweating, especially at night.

If you notice any signs or symptoms of infection, tell your doctor immediately or go to accident and emergency at your nearest hospital.

Things you must not do

Do not take GRANOCYTE to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop giving your injections or lower the dosage without checking with your doctor. For GRANOCYTE to work properly, you have to use it exactly as your doctor has instructed.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with GRANOCYTE.

This medicine helps most people with a low white blood cell count, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following.:

  • bone pain, back pain
  • painful, swollen joints
  • aching muscles, muscle tenderness or weakness not caused by exercise
  • headache and nausea
  • redness, soreness or itchiness around an injection site
  • loss of energy or strength
  • fever

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • skin rash
  • skin reactions, including tender or painful areas or ulcers, blisters, or peeling
  • bleeding or bruising more easily than normal
  • red or purple spots on your skin
  • cough, fever and difficulty in breathing
  • abnormal swelling of the limbs (e.g. legs and feet)
  • pink or dark rust coloured urine
  • bubbly and foamy urine
  • puffiness in face and/or swelling of ankles

The above list includes serious side effects which may require medical attention. Serious side effects are rare.

If any of the following happen, stop using GRANOCYTE and tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
  • shortness of breath
  • light-headedness, dizziness or fainting
  • pinkish, itchy swellings on the skin, also called hives or nettle rash
  • rapid pulse, sweating
  • coughing up blood or mucus
  • pain in the upper left side of your stomach or in your shoulder
  • fever, chest or abdominal pain, malaise and back pain. These could be symptoms of inflammation of your aorta (the large vessel that transports blood from your heart to your body). Tell your doctor if you experience these symptoms.

The above list includes very serious side effects. If you have them, you may have had an allergic reaction to GRANOCYTE. You may need urgent medical attention or hospitalisation.

If you are a healthy donor, and you are or have been given GRANOCYTE for the collection of stem cells, tell you doctor immediately if you notice any of the following:

  • inflammation of the coloured part of the eye
  • chest pain
  • collapse, numbness or weakness of the arms or legs
  • headache, dizziness or confusion, visual disturbances
  • difficulty swallowing, slurred speech or loss of speech
  • gum bleeding or frequent bruising
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • signs of anaemia such as tiredness, being short of breath when exercising and looking pale
  • pain in the upper left side of your stomach or in your shoulder
  • swollen glands in the neck, armpit or groin.

These are serious side effects. These effects have been reported rarely in healthy donors taking GRANOCYTE, and it is not known whether these are definitely caused by GRANOCYTE.

If you or your child are being treated long term for congenital neutropenia, tell your doctor immediately if you develop any of the following:

  • rash or unusual changes to the skin
  • unusual bleeding or bruising.

Some patients may get an enlarged spleen, changes in the number of certain blood cells or bone thinning. Your doctor will monitor you for the appearance of these side effects.

Very rarely, some forms of leukaemia and chromosome disorders have occurred in patients with congenital neutropenia treated with G-CSF. It is not known if this was due to the congenital neutropenia or to the G-CSF. Your doctor will do tests to check for these conditions.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Storage and disposal

Storage

GRANOCYTE will be stored in the pharmacy or on the ward in a cool dry place where the temperature stays below 30°C.

Once GRANOCYTE is dispensed to you, keep it in a place where the temperature stays below 30°C. Short exposure of the vials to elevated temperatures (up to 4 weeks at 40°C) does not affect the product stability.

Do not store GRANOCYTE in the freezer. Freezing can damage some medicines.

Keep prepared solutions of GRANOCYTE in the refrigerator at a temperature between 2−8°C for no longer than 24 hours. As GRANOCYTE does not contain a preservative, there is a risk that any solution prepared more than 24 hours ago may be contaminated with germs and cause an infection.

Keep this medicine in the original pack until it is time to use it. If you take it out of the pack, it may not keep well.

Do not store GRANOCYTE or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine, or the expiry date on the vials has passed, or the prepared solution of GRANOCYTE has been left unrefrigerated, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

GRANOCYTE is a white powder in a glass vial. It is available in two different dosage strengths:

  • GRANOCYTE 34 - 263 micrograms (33.6 million International Units) of lenograstim per vial
  • GRANOCYTE 13 - 105 micrograms (13.4 million International Units) of lenograstim per vial.

Ingredients

GRANOCYTE 34 contains 263 micrograms (33.6 million International Units) of lenograstim as the active ingredient.

GRANOCYTE 13 contains 105 micrograms (13.4 million International Units) of lenograstim as the active ingredient.

It also contains:

  • mannitol
  • polysorbate 20
  • phenylalanine
  • methionine
  • arginine
  • hydrochloric acid.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Pfizer Australia Pty Ltd
Sydney, NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

® GRANOCYTE is a registered trade mark of Chugai Pharmaceutical Co., Ltd. used under licence.

This leaflet was updated in
March 2020

AUST R number(s):

  • GRANOCYTE 13 - AUST R 79436
  • GRANOCYTE 34 - AUST R 79437

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Granocyte

Active ingredient

Lenograstim

Schedule

S4

 

1 Name of Medicine

Lenograstim.

2 Qualitative and Quantitative Composition

Granocyte contains lenograstim, a recombinant glycoprotein equivalent to the human granulocyte colony stimulating factor (G-CSF).
Granocyte 13 contains 105 microgram (13.4 million International Units#) (IU) lenograstim in 1 mL of reconstituted product.
Granocyte 34 contains 263 microgram (33.6 million International Units#) (IU) lenograstim in 1 mL of reconstituted product.
The reconstituted product for both strengths of Granocyte is formulated with a hydrochloric acid buffer at pH 6.5 and contains 2.5% mannitol, 1% arginine, 1% phenylalanine, 0.1% methionine and 0.01% polysorbate 20.

Excipient(s) with known effect.

Phenylalanine.
For the full list of excipients, see Section 6.1 List of Excipients.
# As measured by the GNFS-60 in vitro bioassay in comparison with the WHO International Standard for human G-CSF.

3 Pharmaceutical Form

Granocyte is presented as white cake of lyophilised powder for injection in a glass vial with a rubber stopper and a flip off cap.

4 Clinical Particulars

4.1 Therapeutic Indications

Granocyte is indicated:
to reduce the duration of neutropenia and the severity of infections in patients with nonmyeloid malignancy who have either undergone autologous or allogeneic bone marrow transplantation or undergone treatment with established cytotoxic chemotherapy;
to reduce the incidence of infection associated with established cytotoxic chemotherapy;
to mobilise peripheral blood progenitor cells (PBPCs) either with Granocyte alone, or after myelosuppressive chemotherapy, in order to accelerate haematopoietic recovery by infusion of such cells, after myelosuppressive or myeloablative therapy in patients with non-myeloid malignancies. Granocyte is also indicated to accelerate the engraftment of these cells after their reinfusion;
to mobilise peripheral blood progenitor cells (PBPCs) in healthy donors;
in the treatment of severe congenital neutropenia.

4.2 Dose and Method of Administration

Granocyte 13: 105 microgram (13.4 million IU) per vial is used in patients with body surface area up to 0.7 m2.
Granocyte 34: 263 microgram (33.6 million IU) per vial is used in patients with body surface area up to 1.8 m2.

Dosage.

In PBPC mobilisation following chemotherapy.

After myelosuppressive chemotherapy, Granocyte should be administered daily at the recommended dose of 150 microgram (19.2 million IU) per m2 per day, clinically equivalent to 5 microgram (0.64 million IU) per kg per day, as a subcutaneous (SC) injection starting on the day after completion of chemotherapy until the expected nadir has passed and neutrophil count returns to a normal range compatible with treatment discontinuation.
Leukapheresis should be performed when the postnadir leucocyte count is rising or after assessment of CD34+ cells in the blood with a validated method. For patients who have not had extensive chemotherapy, one leukapheresis is often sufficient to obtain the acceptable minimum yield of PBPC (≥ 2.0 x 106 CD34+ cells/kg).

In PBPC mobilisation with Granocyte alone.

Granocyte should be administered daily at the recommended dose of 10 microgram (1.28 million IU) per kg per day as a SC injection for 4 to 6 days. Leukapheresis should be performed between days 5 and 7. In patients who have not had extensive chemotherapy, one leukapheresis is often sufficient to obtain the acceptable minimum yield of PBPC (≥ 2.0 x 106 CD34+ cells/kg).

In bone marrow transplantation (BMT) and post-PBPC reinfusion.

Granocyte should be administered daily at the recommended dose of 150 microgram/m2/day, clinically equivalent to 5 microgram/kg/day as a SC injection, starting the day following reinfusion of PBPC. In BMT, the recommended dose of Granocyte can also be administered as a 30 minute intravenous (IV) infusion (see Reconstitution and administration below).
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 BMT, 50% of patients will achieve neutrophil recovery. When given postreinfusion of PBPCs, the first dose of Granocyte should be administered at the recommended dose of 150 microgram/m2/day, clinically equivalent to 5 microgram/kg/day, at least 24 hours after cytotoxic chemotherapy has ceased and at least 24 hours after reinfusion of PBPCs. The maximum duration of treatment with Granocyte post-PBPC reinfusion should also be defined according to the period required for achievement of acceptable neutrophil counts (i.e. > 0.5 x 109/L for 3 consecutive days, or > 1 x 109/L for 1 day).

In PBPC mobilisation in healthy donors.

In healthy donors, a 10 microgram/kg daily dose administered subcutaneously for 5-6 days allows a CD34+ cells collection ≥ 3.0 x 106/kg bodyweight with a single leukapheresis in 83% of subjects and with 2 leukaphereses in 97%.

In established cytotoxic chemotherapy.

The recommended dose of Granocyte is 150 microgram (19.2 million IU) per m2 per day, clinically equivalent to 5 microgram (0.64 million IU) per kg per day.
However, data from clinical studies suggest that a dose of 2 microgram (0.256 million IU) per kg per day can reduce the days to neutrophil nadir, increase the total AUC value for neutrophils, and decrease the number of days with a neutrophil count < 1,000 x 106/L in patients. It is a matter of clinical judgment whether patients require this treatment.
Granocyte at the recommended dose should be administered daily as a SC injection starting on the day following completion of chemotherapy. Daily administration of Granocyte should continue until the expected nadir has passed and the neutrophil count returns to within the normal range, which usually occurs within 8 to 14 days after starting treatment.
Even if a transient increase of neutrophil takes place within the first 2 days of treatment, with continuation of treatment the subsequent nadir usually occurs earlier and recovers more quickly.

In severe congenital neutropenia.

Granocyte at 150 microgram/m2/day, clinically equivalent to 5 microgram/kg/day, should be administered as a SC injection. The initial evaluation period of neutrophil recovery should be 7 to 14 days. Induction doses up to 20 microgram (2.56 million IU) per kg may be required. Once obtained, neutrophil recovery may be sustained by continuation of treatment; cautious dose tapering and/or alternate day treatment may be feasible in some patients based on their absolute neutrophil counts (ANC) counts.

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 for either strength of Granocyte.

Children.

Safety and efficacy of Granocyte have been established in patients older than 2 years in BMT, after established cytotoxic chemotherapy and in patients older than 4.5 months with severe congenital neutropenia.

Reconstitution and administration.

Granocyte vials contain no antimicrobial agent.
Product is for single-dose use in one patient only.
Discard any residue.
Aseptically add 1.0 mL water for injections to the Granocyte vial.
Agitate gently until complete dissolution (about 5 seconds). Do not shake vigorously.
Administer immediately by SC or IV route.
For SC administration, Granocyte may be administered as a SC bolus or continuous infusion. The volume of SC injection should not exceed 1.0 mL and the site of injection should be alternated to avoid local bruising/ bleeding.
For IV injection, dilution should be performed in 0.9% sodium chloride solution or 5% glucose. The solution is compatible with polyvinyl chloride bags and glass bottles.
Dilution of Granocyte 13 million IU/mL to a final concentration of less than 0.26 million IU/mL (2 microgram/mL) is not recommended. 1 vial of reconstituted Granocyte 13 million IU/mL should not be diluted in more than 50 mL.
Dilution of Granocyte 34 million IU/mL to a final concentration of less than 0.32 million IU/mL (2.5 microgram/mL) is not recommended. 1 vial of reconstituted Granocyte 34 million IU/mL should not be diluted in more than 100 mL.
Granocyte is compatible with the commonly used giving-sets for injection (polyvinyl chloride) when diluted in sodium chloride 0.9% solution.

4.3 Contraindications

Granocyte should not be administered to patients with known hypersensitivity to the product or its constituents.
Granocyte should not be used to increase the dose intensity of cytotoxic chemotherapy beyond established dosage regimens and time courses since the drug could reduce myelotoxicity but not overall toxicity of cytotoxic drugs.
Granocyte should not be administered concurrently with cytotoxic chemotherapy.
Granocyte should not be administered to patients suffering from myeloid malignancy.

4.4 Special Warnings and Precautions for Use

Patients with severe congenital neutropenia.

Acute myeloid leukaemia (AML) or abnormal cytogenetics have been reported to occur in the natural history of congenital neutropenia without cytokine treatment. Abnormal cytogenetics have been associated with the development of myeloid leukaemia. In patients with congenital neutropenia, it is unknown if therapy with lenograstim accelerates and/or transforms to the development of cytogenetic changes or myeloid leukaemia. Caution should, therefore, be exercised in using Granocyte in patients with congenital neutropenia.
Care should be taken to confirm the diagnosis of severe congenital neutropenia before commencing therapy with Granocyte as it may be difficult to distinguish the disease from myelodysplasia (MDS). The safety and efficacy of Granocyte in the treatment of neutropenia, due to MDS or myeloid leukaemia, have not been established. It is important that serial full blood counts with differential and platelet counts and an evaluation of bone marrow morphology and karyotype be done before commencement of therapy with Granocyte. The use of Granocyte before diagnostic confirmation of severe congenital neutropenia may mask neutropenia as a diagnostic sign of a disease process other than congenital neutropenia.
If a patient with severe congenital neutropenia develops abnormal cytogenetics, the risks and benefits of continuing Granocyte should be carefully considered.

Malignant cell growth.

G-CSF can promote growth of myeloid cells in vitro and similar effects may be seen on some nonmyeloid cells in vitro.
The safety and efficacy of Granocyte administration in patients with myelodysplasia, acute myelogenous leukaemia (AML) or chronic myelogenous leukaemia have not been established. Therefore, because of the possibility of tumour growth, Granocyte should not be used in any myeloid malignancy.
Clinical trials have not established whether Granocyte influences the progression of myelodysplastic syndromes to AML. Caution should be exercised in using Granocyte in any premalignant 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 lenograstim therapy.

Leukocytosis.

A leukocyte count greater than 50 x 109/L has been observed in none of the 174 patients treated with 5 microgram/kg/day (0.64 million IU/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 microgram/kg/day (0.64 million IU/kg/day). No adverse events directly attributable to this degree of leukocytosis have been reported. In view of the potential risks associated with severe leucocytosis, a white blood cell count should, however, be performed twice weekly during Granocyte therapy. If leukocyte counts exceed 10 x 109/L after the expected nadir, Granocyte should be discontinued immediately.
However, during the period of administration of Granocyte for PBPC mobilisation, Granocyte should not be given if the leukocyte count rises to > 50 x 109/L.

Pulmonary adverse effects.

The onset of pulmonary 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 adult respiratory distress syndrome (ARDS). Granocyte should be immediately discontinued and appropriate treatment given.
Pulmonary adverse events (haemoptysis, pulmonary haemorrhage, lung infiltrates, dyspnoea and hypoxia) have been reported in patients and donors receiving lenograstim. In case of suspected or confirmed pulmonary adverse events, discontinuation of treatment with lenograstim should be considered and appropriate medical care given.
Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk.

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).

Splenic rupture.

Splenic rupture or splenomegaly have been reported during peripheral blood stem cell mobilisation with lenograstim and in patients who received lenograstim for neutropenia (see Section 4.1) and the acceleration of haematopoietic recovery post PBPC reinfusion. Changes in haematological parameters and spleen size (e.g. by clinical examination, abdominal ultrasonography) should be monitored. If enlargement of the spleen is observed during therapy with Granocyte, appropriate therapeutic measures should be taken, including discontinuing administration of Granocyte.
A diagnosis of splenic rupture should be considered in donors or patients reporting left upper quadrant abdominal pain or shoulder tip pain.

In bone marrow transplantation.

The effect of Granocyte on the incidence and severity of acute and chronic graft versus host (GVH) disease has not been accurately determined.

With increased doses of chemotherapy.

Safety and efficacy of Granocyte have not been established in the context of intensified chemotherapy. Granocyte should not be used to decrease beyond the established limits intervals between chemotherapy cycles and/or to increase single dosage chemotherapy. Indeed, non-myeloid toxicities have been limiting factors in a phase II chemotherapy intensification trial with Granocyte.

In autologous peripheral blood progenitor cell (PBPC) mobilisation and therapy.

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 myelosuppressive 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 each individual patient.

Prior exposure to cytotoxic agents.

Patients who have undergone extensive prior myelosuppressive therapy, may not show sufficient PBPC mobilisation to achieve the acceptable minimum yield (> 2 x 106 CD34+ cells/kg) and, therefore, adequate haematological reconstitution.
A PBPC reinfusion program should be defined early in the treatment course of the patient and particular attention should be paid to the number of PBPCs mobilised before the administration of high dose chemotherapy. If yields are low, the PBPC reinfusion program should be replaced by other forms of treatment.

Assessment of progenitor cell yields.

Particular attention should be paid to the method of quantitation of progenitor cell yields as the results of flow cytometric analysis of CD34+ cell numbers vary among laboratories.
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. However, the minimum yield of CD34+ cells is not well defined. Yields higher than ≥ 2.0 x 106 CD34+ cells/kg are associated with more rapid recovery of haematopoiesis.

In healthy donors.

PBPC mobilisation is a procedure without direct benefits for healthy donors and should only be performed in accordance with local regulations.
The efficacy and safety of Granocyte has not been assessed in healthy donors aged over 60 years or below 18 years and therefore the procedure cannot be recommended in these subjects.
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 leucocytosis (WBC > 50 x 109/L) was observed in 24% of subjects studied.
There have been isolated cases of splenic rupture following administration of granulocyte-colony stimulating factors (G-CSFs) (see Section 4.4 Special Warnings and Precautions for Use, Splenic rupture).
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 subjects 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 and, therefore, consideration should be given to the adequacy of venous access when selecting donors.
Transient cytogenetic modifications have been observed in normal donors following G-CSF use. The significance of these changes is unknown.
Data on long-term follow-up of donors are available on a small number of subjects. After a period of up to six years, no emerging long-term sequelae adverse events have been reported. Nevertheless, a risk of promotion of a malignant myeloid clone is possible. 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. There have been rare reports of myeloproliferative disorder and acute myeloid leukaemia in PBPC donors who received a granulocyte colony stimulating factor preparation, although a causal relationship has not been established. Therefore, it is recommended that systematic records and tracking of the stem cell gifts be made by the apheresis centres.

In recipients of allogeneic peripheral blood progenitor cells mobilised with Granocyte.

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

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 characterised by cumulative or predominant myelotoxicity with respect to the platelet lineage (nitrosourea, mitomycin) has not been established. Administration of Granocyte might even enhance the toxicities of these agents, particularly with respect to platelets.

In peripheral stem cells or bone marrow transplantation.

Special attention should be paid to platelet recovery in patients recovering from chemotherapy induced myelotoxicity or from bone marrow transplantation.

Other precautions.

In patients with substantially reduced myeloid progenitor cells (e.g. due to prior extensive radiotherapy/ chemotherapy), neutrophil response is sometimes diminished and the safety of Granocyte has not been established.
In patients receiving nitrosoureas without bone marrow rescue, efficacy and safety of Granocyte have not been established.
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.
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.
Granocyte contains phenylalanine, which may be harmful for people with phenylketonuria.
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.
Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and 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.

Use in hepatic impairment.

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

Use in renal impairment.

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

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

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 Interactions with Other Medicines and Other Forms of Interactions

The safety and efficacy of Granocyte given on the same day as myelosuppressive cytotoxic chemotherapy have not been established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, the use of Granocyte should not precede or overlap the administration of cytotoxic chemotherapy. It is recommended that Granocyte should start on the day following completion of chemotherapy.
Possible interactions with other haematopoietic growth factors and cytokines have yet to be investigated in clinical trials.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproduction and fertility were unaffected by Granocyte in mice at doses up to 1,000 microgram/kg/day IV and in rats at doses up to 100 microgram/kg/day IV.
(Category B3)
Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
Granocyte has been shown to have adverse effects in pregnant rabbits when given in doses of 100 microgram/kg/day IV. There are no adequate and well controlled studies in pregnant women.
In rabbits, increased abortion and embryolethality were observed in animals treated with Granocyte at 100 microgram/kg/day IV. Fetal weights were also reduced with this dose and to a lesser extent with 10 microgram/kg/day. However, reductions in maternal weight gain and food consumption were also seen with both doses. Similar adverse findings were not seen in a corresponding rat study with the same doses and there was no evidence for teratogenicity in either species.
 Studies in animals have shown that Granocyte is excreted in the milk of lactating rats. It is not known whether Granocyte is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Granocyte is administered to a nursing woman.

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 Adverse Effects (Undesirable Effects)

Frequency of adverse reactions issued from clinical trials and postmarketing surveillance data. Very common (≥ 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); not known (cannot be estimated from the available data). See Table 1.

In BMT.

Special attention should be paid to platelet recovery since in double blind placebo controlled trials the mean platelet count may have been slightly lower in patients treated with Granocyte as compared to placebo vehicle. However, this did not result in an increase in incidence of adverse experiences related to blood loss, and the median number of days following BMT to last platelet infusion was similar in both Granocyte and placebo groups.
In placebo controlled trials, the most frequently reported side effects (> 15% in at least one treatment group) occurred with equal frequency in patients treated with Granocyte or placebo. These were infection/ inflammatory disorder of buccal cavity, fever, diarrhoea, rash, abdominal pain, vomiting, alopecia, sepsis and infection.
In placebo controlled trials after BMT, the incidence of GVH disease was similar in patients treated with Granocyte or placebo.

In PBPC mobilisation and therapy.

In clinical practice, PBPCs are replacing BMT for a number of reasons including the reduction in time to platelet recovery. In the clinical trials carried out in patients and healthy volunteers undergoing PBPC mobilisation, as well as in patients undergoing PBPC reinfusion, Granocyte was well tolerated. Side effects were generally mild. The most frequently encountered adverse events were bone pain, headache and malaise. There have been isolated cases of splenic rupture in subjects undergoing peripheral blood stem cell mobilisation with granulocyte colony stimulating factors (G-CSFs) (see Section 4.4 Special Warnings and Precautions for Use, Splenic rupture).

In chemotherapy induced neutropenia.

In placebo controlled trials, Granocyte appeared safe, with equal incidence of reported adverse experiences in patients treated with Granocyte or placebo. The most commonly reported side effects were alopecia, nausea, vomiting, fever, headache, similar to that observed in cancer patients treated with chemotherapy.
The safety of the use of Granocyte with antineoplastic agents characterised by cumulative or predominant myelotoxicity with respect to the platelet lineage (nitrosourea, mitomycin) has not been established. Administration of Granocyte might even enhance the toxicities of these agents, particularly with respect to platelets.
A higher incidence of bone pain (about 10% higher), usually controlled with simple analgesics such as paracetamol, and injection site reaction (about 5% higher), was reported when patients were treated with Granocyte.

In severe congenital neutropenia.

Special attention should be paid to the possible occurrence of any of the following during long-term treatment: cutaneous rash/ risk of vasculitis, leukocytosis, thrombocytopenia, splenomegaly, potential transformation to a myeloid malignancy, risk of osteopenia.
Cytogenetic abnormalities, transformation to MDS and AML have been observed in patients treated with G-CSF preparations for congenital neutropenia.
Based on the analysis of long-term data on patients treated with another brand of G-CSF, the greatest risk of developing these abnormalities (MDS, AML, cytogenetic abnormalities) seems to be in the subset of patients with congenital neutropenia. In patients with congenital neutropenia treated with G-CSF for up to 5 years, the rate of MDS and AML is reported to be fewer than 3 cases per 100 patient years of exposure. In patients with noncongenital types of neutropenia (cyclic and idiopathic), the rate is fewer than 1 case per 100 patient years of exposure. Leukaemic transformation has also been observed in congenital neutropenia patients prior to the use of G-CSF. In patients treated with G-CSF who had previously documented normal cytogenetic evaluations, cytogenetic abnormalities, including monosomy 7, have been reported.
It is unknown whether the development of abnormalities, such as MDS or AML, is related to chronic daily administration of G-CSF or to the natural history of congenital neutropenia. It is therefore recommended that an annual bone marrow and cytogenetic evaluation should be considered in patients with congenital neutropenia.

In healthy donors.

There have been rare reports of myeloproliferative disorder and acute myeloid leukaemia in PBPC donors who received a granulocyte colony stimulating factor preparation, although a causal relationship has not been established (see Section 4.4 Special Warnings and Precautions for Use, 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 and LDH. Other adverse events reported in healthy donors, regardless of causality: cerebrovascular disorder, myocardial infarction, cardiac arrest, iritis, anaphylactoid reactions, gouty arthritis and non-Hodgkin's lymphoma.

Other adverse effects.

Capillary leak syndrome which can be life threatening if treatment is delayed has been reported uncommonly in the postmarketing setting following administration of granulocyte-colony stimulating factors, mostly in cancer patients undergoing chemotherapy.
Pulmonary infiltrates have been reported in some cases with an outcome of respiratory failure or ARDS, which may be fatal. Pleural effusion has also been reported.
Arthralgia has been reported.

Post-marketing experience relevant to all indications.

Cases of aortitis have been reported rarely (> 1/10,000 and < 1/1,000) in cancer patients and in healthy subjects treated with filgrastim.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

In animals, acute toxicity studies (up to 1,000 microgram/kg/day in mice) and subacute toxicity studies (up to 100 microgram/kg/day in monkeys) showed the effects of overdose were restricted to an exaggerated and reversible pharmacological effect.
In humans, doses up to 40 microgram/kg/day were not associated with toxic side effects except musculoskeletal pain.
The effects of Granocyte overdosage have not been established. 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 microgram/kg/day (5.12 million IU/kg/day) on the 5th day of treatment. In humans, doses up to 40 microgram/kg/day were not associated with toxic side effects except musculoskeletal pain.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Cytokines, ATC code: L03AA10.

Mechanism of action.

Granocyte (lenograstim) belongs to the cytokine group of biologically active proteins which regulate cell differentiation and cell growth.
G-CSF is a factor which stimulates the neutrophil precursor cells as demonstrated by the CFU-S and CFU-GM cell count increases in peripheral blood in the mouse. Granocyte induces a marked increase in peripheral blood neutrophil counts within 24 hours.
Elevations of neutrophil count are dose dependent over the 1 to 10 microgram/kg/day range. At the recommended dose (5 microgram/kg/day), 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 have undergone bone marrow transplantation (BMT) or who are treated with cytotoxic chemotherapy leads to significant reductions in duration of neutropenia and severity of infections.

Clinical trials.

In peripheral blood progenitor cell mobilisation and therapy.

Use of Granocyte, either alone or after chemotherapy mobilises haematopoietic progenitor cells into the peripheral blood. These peripheral blood progenitor cells (PBPCs) can be harvested and infused after 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 accelerate the reconstitution of haematopoiesis and reduce the time to engraftment, leading to a marked decrease in the number of days to platelet independence when compared to bone marrow transplantation.
In an open label phase II study, SC Granocyte 10 microgram/kg/day was administered to 24 patients after standard or intensified induction for advanced breast cancer. The level of granulocyte-monocyte colony forming cells (GM-CFC) was higher after one course of chemotherapy plus Granocyte than after the initial lenograstim alone. Mobilisation was not affected by the chemotherapy dose levels used. Progenitor cell mobilisation was maximal between 6 and 7.5 days after Granocyte alone and between 11 and 13 days after chemotherapy plus Granocyte coinciding with the peak white cell counts obtained. The median number of GM-CFC collected in a single apheresis was 2.17 x 105/kg (n = 9) after cycle 1, and 1.7 x 105/kg (n = 13) after any cycle. This study demonstrated clearly the ability of Granocyte to mobilise progenitor cells into the circulation, and showed that the combination of chemotherapy and Granocyte mobilised more colony forming cells than lenograstim alone. In another open label phase II study, the ability of reinfused Granocyte primed PBPC together with Granocyte postmoderate intensity chemotherapy to facilitate platelet recovery in 21 advanced breast cancer patients, was investigated. Each patient received a 6 day course of SC Granocyte 150 microgram/m2/day prior to commencing an intensified FAC regimen. One group of patients had Granocyte only, a second group had Granocyte plus PBPC collected after cycle 1, a third group had Granocyte plus PBPC contained in 450 mL blood and collected after steady state and next 5 cycles and the fourth group had PBPC collected in the steady state after Granocyte alone (no Granocyte given after FAC chemotherapy). The peak levels of CD34+ cells and GM-CFC found in the blood after Granocyte alone were 32 x 106/L and 7.2 x 105/L, respectively and occurred around day 6. This study confirms that Granocyte alone at a dose of 150 microgram/m2/day can mobilise progenitor cells; and chemotherapy plus Granocyte yields higher progenitor cell levels although the levels decline after repeated administration of chemotherapy.
A phase III multicentre study had been undertaken in 90 patients with Hodgkin's disease and non-Hodgkin's lymphoma treated with ablative chemotherapy (BEAM). The first part of the study was nonrandomised where patients were mobilised with 1.5 g/m2 cyclophosphamide followed by SC Granocyte 263 microgram/day from the day after cyclophosphamide (day 2) until day 10. PBPCs were harvested by leukapheresis on days 10 and 11. In the second part of the study, patients were randomised to receive SC Granocyte 263 microgram/day, or no growth factor, from day 1 posthigh dose therapy (BEAM) and PBPC reinfusion (day 0), until neutrophil recovery to > 0.5 x 109/L for 3 days or > 1 x 109/L for 1 day. Of the 62 evaluable patients, 34 received Granocyte and 28 no growth factor. There was a significant difference observed between the treatment groups (p = 0.0001) in the time to neutrophil recovery. The median time to neutrophil recovery was 9 days in the Granocyte arm versus 13 days in the no growth factor arm. Similarly, there was a significant difference between the treatment groups for days to hospitalisation (p = 0.0002). Patients receiving Granocyte stayed in hospital for a median of 13 days compared with patients receiving no Granocyte who stayed in hospital a median of 15.5 days. The first part of the study confirmed that the combination of cyclophosphamide and Granocyte 1 vial (263 microgram)/day is an effective mobilisation regimen in most patients with lymphoma. The second part of the study indicates that the use of Granocyte 1 vial (263 microgram)/day posthigh dose chemotherapy and reinfusion of PBPCs, shortens the period of neutropenia and decreases the number of days of hospitalisation.

In healthy donors.

The efficacy of Granocyte for PBPC mobilisation has been demonstrated in 4 studies involving a total of 124 healthy donors. In these studies, 106 subjects received the proposed dose of 10 microgram/kg/day subcutaneously for 5-6 days, 76 of whom underwent leukapheresis.
The minimum progenitor cell yield considered to be necessary for successful engraftment in autologous PBPC transplantation is 2.0 x 106 CD34+ cells/kg. The median yields obtained in all four studies in healthy donors were found to be well above this level. In the largest study, CSF-312 (n = 62), Granocyte was found to mobilise progenitor cells in the majority of normal individuals to a level such that > 3 x 106/kg CD34+ could be collected in one pheresis.
Study GCS-306, a phase I randomised crossover study in 32 healthy male volunteers, investigated the ability of Granocyte and Neupogen (filgrastim) to mobilise PBPCs when used at doses of 10 microgram/kg/day for five days. Although peak levels of white blood cell (WBC) counts were almost identical during the first period of therapy with either agent, peak PBPC values and leukapheresis yields were significantly higher in patients treated with Granocyte, as demonstrated in Table 2.

In established cytotoxic chemotherapy.

A cross-over comparison of the efficacy of subcutaneously administered Granocyte at 2 and 5 microgram/kg/day during two consecutive cycles of a standard dose of myelosuppressive chemotherapy in patients with nonleukaemic malignancy has shown that both doses of Granocyte provided similar levels of prophylaxis against the incidence, severity and duration of neutropenia and infectious complications.

In severe congenital neutropenia.

A European phase II open label multicentre study was conducted using lenograstim in 19 patients suffering from congenital agranulocytosis, a form of severe chronic neutropenia. The patients were of both sexes ranging in age from 4.5 months to 23 years with a median of 5 years, and the disease was of sufficient severity as assessed by a recent history of infection, either recurrent under prophylactic antibiotic therapy or having led to hospitalisation. The treatment period ranged from 4 to 35 months (median duration of 27 months).
Induction doses of lenograstim 5 microgram/kg/day by SC injection induced a significant increase in absolute neutrophil counts (ANC ≥ 1,000/microlitre) in 15 patients, the remaining 4 required doses of 10-20 microgram/kg/day. Stable neutrophil counts above 0.5 x 109/L were achieved in 18 of the 19 patients and mostly obtained at a maintenance dose of 5 microgram/kg/day. Intermittent treatment was possible in a minority of patients, usually those who achieved stable neutrophil counts at low dose levels, often below 5 microgram/kg/day.
The frequency and severity of infections were markedly reduced in all but one patient. Growth and weight were seen to increase in line with observed prior growth rates. The number of curative antibiotic therapies and hospitalisations were reduced. Objective and subjective measurements of the quality of life also showed some improvement.
Despite prolonged lenograstim exposure, there were very few adverse events related to lenograstim administration. The main ones noted in this study were leucocytosis, mild hyperuricaemia, erythema at the site of injection, lumbar pain, splenomegaly and grade I thrombocytopenia. In only one patient was treatment with lenograstim discontinued; this patient, on three occasions, developed a rash which was thought to be vasculitis. However, the biopsy slide was subsequently re-examined and the diagnosis changed to acute suppurative pustulosis which subsequently recovered.

5.2 Pharmacokinetic Properties

The pharmacokinetics of Granocyte show dose and time dependencies.
Following SC administration of Granocyte 5 microgram/kg/day to healthy volunteers, peak plasma concentrations are obtained at 6 ± 2.6 hours.
At the end of repeated dosing (IV and SC routes), peak serum concentrations are proportional to the injected dose. Repeated dosing with Granocyte by both injection routes resulted in no evidence of drug accumulation.
The absolute bioavailability of SC Granocyte decreases in a dose-dependent manner from approximately 62% to 24% in the 0.5 - 10 microgram/kg dose range. At the recommended dose (5 microgram/kg/day), the absolute bioavailability of Granocyte is 30 ± 5% and the apparent distribution volume (Vd area) is approximately 52 ± 5 mL/kg body weight.
During multiple SC dosing, peak serum concentrations of Granocyte are close to 100 picogram/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 Granocyte recovered in serum.
The pharmacokinetic profile of Granocyte is similar in healthy volunteers and cancer patients with elimination half-life (t1/2β) values of 2.3 - 3.3 hrs (volunteers); 2.8 - 7.5 hrs (cancer patients) following SC administration and 0.8 - 2.1 hrs (volunteers); 1.1 - 4.0 hrs (cancer patients) following IV administration.
Plasma clearance of lenograstim increased 3-fold (from 50 up to 150 mL/min) during repeated SC dosing. Granocyte is poorly excreted in urine as intact compound (less than 1% of the dose) and is considered to be metabolised to peptides.

5.3 Preclinical Safety Data

Genotoxicity.

Lenograstim was not mutagenic in Salmonella typhimurium, did not increase the frequency of chromosomal aberrations in cultured Chinese hamster lung cells, and was negative in a mouse micronucleus test.

Carcinogenicity.

No carcinogenicity studies have been conducted with Granocyte.

6 Pharmaceutical Particulars

6.1 List of Excipients

Arginine, hydrochloric acid, mannitol, methionine, phenylalanine, polysorbate 20.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
After reconstitution in 1.0 mL Water for Injections as recommended, the resultant solution is stable for 24 hours at 25°C. No decrease in activity was observed after dilution to a final concentration of not less than 0.26 million IU/mL (2 microgram/mL) for Granocyte 13 or 0.32 million IU/mL (2.5 microgram/mL) for Granocyte 34 when the dilution was stored at temperatures up to 30°C for 24 hours.
To reduce microbiological hazard, it is recommended to use reconstituted solutions as soon as practicable after dilution and if storage is necessary, to hold at 2-8°C for not more than 24 hours.

6.4 Special Precautions for Storage

Granocyte vials should be stored below 30°C.
Short exposure of the vials to elevated temperatures (up to 4 weeks at 40°C) does not affect the product stability.

6.5 Nature and Contents of Container

Granocyte is presented as a white cake (lyophilised powder) in a 5 mL Type I glass vial (single pack) with an elastomeric stopper, aluminium seal and flip-off top.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Lenograstim is expressed in a mammalian host cell system, Chinese hamster ovary (CHO) cells. Lenograstim has a molecular weight of about 20,000 Daltons and consists of 174 amino acids and approximately 4% carbohydrate. The amino acid sequence analysis of lenograstim reveals that it is identical to native G-CSF.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription only medicine).

Summary Table of Changes