Consumer medicine information

Zarzio

Filgrastim

BRAND INFORMATION

Brand name

Zarzio

Active ingredient

Filgrastim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zarzio.

SUMMARY CMI

Zarzio®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Zarzio?

Zarzio contains the active ingredient filgrastim. Zarzio is used to encourage your bone marrow to produce more neutrophils, a type of white blood cell. You may have been prescribed Zarzio because you are receiving treatment for cancer, are receiving a bone marrow or stem cell transplant, are donating stem cells for another person, are suffering from severe chronic neutropenia or are receiving medicines for HIV infection. For more information, see Section 1. Why am I using Zarzio? in the full CMI.

2. What should I know before I use Zarzio?

Do not use if you have ever had an allergic reaction to Zarzio or any of the ingredients listed at the end of the CMI, or to any medicines or products that are produced using the bacteria E.coli.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Zarzio? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zarzio and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Zarzio?

Zarzio is injected under the skin (subcutaneous). More instructions can be found in Section 4. How do I use Zarzio? in the full CMI.

5. What should I know while using Zarzio?

Things you should do
  • Remind any doctor, nurse, dentist or pharmacist you visit that you are using Zarzio.
  • Keep all of your doctor's appointments so that your health can be monitored.
  • Tell your doctor straight away if you become pregnant.
  • Go straight to your hospital if you notice any signs or symptoms of infection.
Things you should not do
  • Do not use Zarzio to treat any other complaints unless your doctor tells you to.
Driving or using machines
  • Be careful driving or using any machines or tools until you know how Zarzio affects you.
Looking after your medicine
  • Keep Zarzio in a refrigerator at a temperature of 2°C to 8°C.
  • Keep your medicine in its pack until it is time to use it. Protect it from light.

For more information, see Section 5. What should I know while using Zarzio? in the full CMI.

6. Are there any side effects?

Common side effects include bone, back, muscle, joint, mouth or throat pain; swelling or stiffness of joints; muscle spasms; abdominal discomfort; diarrhoea; constipation; nausea; vomiting; severe nose bleeds; reddish or purplish bumps or blotches, mouth ulcers; numbness; tingling in the hands and feet; injection site reactions; cough; hair loss; headache; looking pale; loss of appetite; unusual weakness; difficulty sleeping. Serious side effects include rash, itching or hives; shortness of breath, wheezing, difficulty, or rapid breathing; tiredness, fever; easy bruising or bleeding; coughing up blood; swelling; faintness; rapid pulse or sweating; painful skin lesions; chest pain; left shoulder pain; pain in the upper left side of the stomach; swelling of your stomach-area; reduced urination; blood in the urine. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Zarzio®

Active ingredient(s): filgrastim

Consumer Medicine Information (CMI)

This leaflet provides important information about using Zarzio. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Zarzio.

Where to find information in this leaflet:

1. Why am I using Zarzio?
2. What should I know before I use Zarzio?
3. What if I am taking other medicines?
4. How do I use Zarzio?
5. What should I know while using Zarzio?
6. Are there any side effects?
7. Product details

1. Why am I using Zarzio?

Zarzio contains the active ingredient filgrastim. Zarzio belongs to a group of medicines called cytokines and is a copy of a substance normally present in your body, called Granulocyte Colony Stimulating Factor or G-CSF. Using gene technology, Zarzio is produced in a specific type of bacteria, called E. coli. G-CSF is produced in the bone marrow and assists in the production of neutrophils, which are a type of white blood cell. Neutrophils help the body fight infections by surrounding and destroying the bacteria that cause them. G-CSF also helps neutrophils to do this work better. Zarzio works by encouraging the bone marrow to produce more neutrophils.

Zarzio can be used:

  • to increase the number of white blood cells after treatment with chemotherapy to help prevent infections;
  • to increase the number of white blood cells after a bone marrow transplant to help prevent infections;
  • before high-dose chemotherapy to make the bone marrow produce more stem cells which can be collected and given back to you after your treatment. These can be taken from you or from a donor. The stem cells will then go back into the bone marrow and produce blood cells;
  • to increase the number of white blood cells if you suffer from severe chronic neutropenia to help prevent infections;
  • in patients with advanced HIV infection which will help reduce the risk of infections

2. What should I know before I use Zarzio?

Warnings

Do not use Zarzio if:

  • you are allergic to filgrastim, any of the ingredients listed at the end of this leaflet or any medicines or products are produced using the bacteria E.coli. Always check the ingredients to make sure you can use this medicine.
  • at the same time as your chemotherapy or radiotherapy.
  • in the 24 hours before or after you receive your chemotherapy, radiotherapy, bone marrow transplant or stem cell transplant.
    This is because these types of treatments may stop Zarzio from increasing the number of infection-fighting neutrophils.

Check with your doctor if you:

  • have any allergies to any other medicines, foods, preservatives or dyes
  • have any other medical conditions
    - a medical condition affecting the bone marrow or blood
    - family history of a genetic disorder
    - sickle cell disease
    - problems with your kidneys, liver, heart or other organs
    - previous treatment for cancer
    - any infections, cancers or tumours.
  • take any medicines for any other condition
  • are not sure whether you should use Zarzio.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if the active ingredient in Zarzio passes into the milk.

Use in Children

  • There is limited experience with the use of Zarzio in children. Your doctor will discuss the risks and benefits of using it in children.

3. What if I am taking other medicines?

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

Some medicines may interfere with Zarzio and affect how it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Zarzio.

4. How do I use Zarzio?

How much to inject

  • Your doctor will tell you how much Zarzio to use. How much you will need to use will depend on the reason for your treatment, your body weight and the number of neutrophils in your blood.
  • For Zarzio to work properly, you have to use it exactly as your doctor has instructed.
  • Follow the instructions provided and use Zarzio until your doctor tells you to stop.

When to use Zarzio

  • Zarzio should be used at the same time each day.
  • Your doctor will tell you when to begin your treatment and when to stop.
  • Your doctor will tell you how many injections you need each week and on which days they should be given.
    - Patients receiving chemotherapy or who have received a bone marrow or stem cell transplant are only required to use Zarzio for short periods of time until the number of infection-fighting neutrophils are restored (usually 1 to 3 weeks).
    - Stem cell donors should receive Zarzio treatment for 4 to 5 days.
    - Patients with severe chronic neutropenia are required to use Zarzio regularly and for a long period of time, to keep the number of infection-fighting neutrophils at a normal level.
    - Patients with HIV infection need to use Zarzio daily until their neutrophil numbers are normal. Usually, the dose is then reduced to three injections per week to maintain the neutrophil numbers.

How to use Zarzio

  • Zarzio is given by injection. This can be either:
    - into the tissues just below the skin, called a subcutaneous injection, or
    - into the vein, called an intravenous injection
  • Intravenous injections will be given by a doctor or nurse.
  • For subcutaneous injections, in some instances, your doctor, nurse or pharmacist may suggest that you or your carer be taught how to administer the injection. This will allow you to have your Zarzio injection at home.
  • Follow all directions given to you by your doctor, nurse or pharmacist carefully. They may differ from the information contained in this leaflet.
  • If you do not understand the instructions, ask your doctor, nurse or pharmacist for help.

Where to inject Zarzio

The best injection sites are:

  • your abdomen, except for the area around the navel (belly button) or
  • the front side of your thighs.

The sites are shown in the pictures below.

  • Change the injection site each time you inject to avoid soreness at any one site.

Things to do before you inject

Make sure you have all materials you need for your injection:

  • a new Zarzio syringe
  • an alcohol swab
  • a puncture-resistant sharps container.

Follow these instructions exactly to help avoid contamination and possible infection.

If you are unsure, check with your doctor, nurse or pharmacist.

  1. Find a clean, flat working surface, such as a table, where you can inject undisturbed.
  2. Remove the syringe from the refrigerator. For a more comfortable injection, leave at room temperature for approximately 30 minutes. Do not warm Zarzio in any other way (e.g. do not warm in a microwave or hot water).
  3. Check that the syringe has NOT been used before.
  4. Do not shake the syringe. If the Zarzio solution appears frothy or bubbly, allow the syringe to sit undisturbed for a few minutes to reduce the froth or bubbles before measuring your dose.
  5. Do not remove the needle cover until you are ready to inject.
  6. Check the expiry date on the label. Do not use if the date has passed the last day of the month shown.
  7. Check the appearance of the solution. The solution should be clear and colourless or slightly yellow in colour. If it is cloudy, coloured or there are clumps or flakes, you must not use it.
  8. Wash and dry your hands thoroughly.

How to prepare for your injection

  1. Hold the syringe vertically with the needle pointing up, this helps reduce the amount of medicine that may leak out of the needle. Carefully remove the needle cover, taking care not to touch the exposed needle.
  2. Check the dose (in mL) that your doctor has prescribed and locate the correct volume mark on the syringe barrel. Carefully push the plunger until the grey upper edge of the plunger reaches the correct volume mark. This will push the air and any excess liquid out of the syringe.
  3. Double-check that you have the correct dose.

How to inject

This section contains information on how to give yourself an injection of Zarzio. It is important that you do not try to give yourself the injection unless you have received special training from your doctor or nurse. Zarzio is provided with or without a needle safety guard and you will be shown how to use this by your doctor or nurse. If you are not sure about giving the injection or you have any questions, please ask your doctor or nurse for help.

  1. Wash your hands
  2. Remove one syringe from the pack and remove the protective cap from the injection needle. Syringes are embossed with graduation rings in order to enable partial use if required. Each graduation ring corresponds to a volume of 0.1 ml. If partial use of a syringe is required, remove unwanted solution before injection.
  3. Clean the skin at the injection site using an alcohol wipe.
  4. Form a skin fold by pinching the skin between thumb and forefinger.
  5. Insert the needle into the skin fold with a quick, firm action. Inject the Zarzio solution as you have been shown by your doctor. You should check with your doctor or pharmacist if you are not sure.

Pre-filled syringe without needle safety guard

  1. Always keeping your skin pinched, depress the plunger slowly and evenly.
  2. After injecting the liquid, remove the needle and let go of your skin.
  3. Put the used syringe in the disposal container. Use each syringe only for one injection.

Pre-filled syringe with needle safety guard

  1. Always keeping your skin pinched, depress the plunger slowly and evenly until the entire dose has been given and the plunger cannot be depressed any further. Do not release the pressure on the plunger!
  2. After injecting the liquid, remove the needle while maintaining pressure on the plunger and then let go of your skin.
  3. Let go of the plunger. The needle safety guard will rapidly move to cover the needle.
  4. Discard any unused product or waste material. Only use each syringe for one injection

Do not change the dose or the way you inject Zarzio without consulting your doctor. Always follow your doctor's instructions.

If you forget to use Zarzio

If you miss your scheduled dose, inject it as soon as you can - provided that it is still on the same day.

If you miss a whole day before you remember to inject yourself, do not take a 'catch-up' dose or increase your next dose.

Talk to your doctor, nurse or pharmacist as soon as possible about the missed dose.

If you use too much Zarzio

If you think that you have used too much Zarzio, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Zarzio?

Things you should do

  • Remind any doctor, dentist, pharmacist or nurse you visit that you are using Zarzio.
  • Keep all of your doctor's appointments so that your health can be monitored. Your doctor may order blood tests to check the levels of infection-fighting neutrophils and other blood cells.
    Treatment with Zarzio leads to changes in the numbers of certain blood cells.
    Blood tests may also be undertaken after you have completed your Zarzio treatment until your blood cells have returned to normal levels.

Call your doctor straight away if you:

  • become pregnant

Go straight to your hospital if you:

  • Notice any signs or symptoms of infection.
    There are many ways an infection may show itself. Symptoms of an infection include: fever (a temperature of 38.2°C or greater, or as your doctor suggests), chills, rash, sore throat, diarrhoea, earache, difficult or painful breathing, coughing or wheezing.

Things you should not do

  • Do not use Zarzio to treat any other complaints unless your doctor tells you to.
  • Do not give Zarzio to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Zarzio affects you.

The effects on your ability to drive or use machines whilst taking Zarzio are not known.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

  • Keep Zarzio in a refrigerator at a temperature of 2°C to 8°C.
  • Exposure to room temperature for up to 8 days will not harm Zarzio.
  • Keep Zarzio in its carton until it is time to use it. Protect it from light.
  • Keep it where children cannot reach it.

When to discard your medicine

Once you have injected Zarzio, do not put the cover back on the used syringe.

Discard the used syringe into an approved, puncture-resistant, sharps container and keep it out of the reach of children.

Never put used syringes into your normal household rubbish bin.

Dispose of the full puncture resistant sharps container as instructed by your doctor, nurse or pharmacist.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Muscle and Skeleton:
  • temporary bone pain, such as in the lower back or in the long bones of the arms or legs.
    This pain is usually relieved with non-prescription painkillers, like paracetamol. If you continue to have bone pain even after having taken this form of pain relief, you should speak to your doctor, as you may need a prescription medicine.
  • back pain
  • pain, swelling, warmth or stiffness of joints
  • worsening of existing arthritis
  • muscle pain
  • muscle spasms
Gut and Digestion:
  • abdominal discomfort
  • diarrhoea or constipation
  • nausea (feeling sick) and/or vomiting
Blood:
  • pink, red or blue/purple spots or bumps on the skin
  • bleeding or bruising more than usual, severe nose bleeds
  • reddish or purplish blotches under the skin
Eyes, ears and mouth:
  • sore throat
  • sore mouth, mouth ulcers
Nervous System:
  • numbness
  • tingling in the hands and feet
Skin:
  • redness, swelling or itching at the site of injection
  • skin disorders - worsening of existing symptoms
  • skin rash or red, itchy spots
  • swelling of hands, legs, ankles, feet or any other part of the body
General:
  • cough
  • hair loss
  • headache
  • looking pale
  • loss of appetite
  • unusual weakness
  • difficulty sleeping
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
General:
  • chest pain
  • fever
  • general feeling of tiredness
  • left shoulder tip pain
  • frequent infections
  • tiredness, fever and easy bruising or bleeding.
  • dizziness or feeling light headed
  • faintness
  • rapid pulse or sweating
Lungs and upper airways:
  • coughing up blood, bleeding from the lung
  • breathing problems such as shortness of breath, rapid breathing
Gut, Digestion and Urine-related:
  • pain in the upper left side of the stomach (abdomen)
  • swelling of your stomach-area (abdomen) and feeling of fullness
  • less frequent urination
  • blood in the urine
Skin
  • fever and painful skin lesions, most commonly on your arms, legs and sometimes on your face and neck
  • swelling or puffiness
Signs of an allergic reaction:
  • rash over a large area of the body, itching or hives
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Zarzio contains

Active ingredient
(main ingredient)		filgrastim (rbe)
Other ingredients
(inactive ingredients)
  • glutamic acid
  • sorbitol
  • polysorbate 80
  • sodium hydroxide (for pH adjustment)
  • water for injections.
Potential allergensThe needle cover on the pre-filled syringe contains a derivative of latex.

Do not take this medicine if you are allergic to any of these ingredients.

What Zarzio looks like

Zarzio® is a colorless, to slightly yellowish solution and supplied as a ready to use syringe.

Available in the following strengths:

  • 300 micrograms of filgrastim in a volume of 0.5 mL (AUST R 195066);
  • 480 micrograms of filgrastim in a volume of 0.5 mL (AUST R 195065).

The syringes are packed in pack sizes of 1, 5 and 10.

Not all strengths or presentations may be marketed.

Who distributes Zarzio

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Tel: 1800 726 369

This leaflet was prepared in October 2023.

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Zarzio

Active ingredient

Filgrastim

Schedule

S4

 

1 Name of Medicine

Filgrastim (rbe). A recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) derived from E. coli.

2 Qualitative and Quantitative Composition

Zarzio 300 microgram/0.5 mL solution for injection.

Each pre-filled syringes contains either 300 microgram (30 MU) filgrastim at a fill volume of 0.5 mL.

Zarzio 480 microgram/0.5 mL solution for injection.

Each pre-filled syringes contains 480 microgram (48 MU) filgrastim at a fill volume of 0.5 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zarzio 300 microgram/0.5 mL and 480 microgram/0.5 mL solution for injection is a sterile, clear, colourless to slightly yellowish, preservative-free liquid for parenteral administration.
Zarzio is available in single use pre-filled syringes.

4 Clinical Particulars

4.1 Therapeutic Indications

Zarzio is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs in doses not usually requiring bone marrow transplantation.
Zarzio is indicated for reducing the duration of neutropenia and clinical sequelae in patients undergoing induction and consolidation chemotherapy for acute myeloid leukaemia (AML).
Zarzio is indicated for the mobilisation of autologous peripheral blood progenitor cells alone, or following myelosuppressive chemotherapy, in order to accelerate neutrophil and platelet recovery by infusion of such cells after myeloablative or myelosuppressive therapy in patients with nonmyeloid malignancies.
Zarzio is indicated for the mobilisation of peripheral blood progenitor cells, in normal volunteers, for use in allogeneic peripheral blood progenitor cell (PBPC) transplantation.
In patients receiving myeloablative chemotherapy, Zarzio is indicated for reducing the duration of neutropenia and clinical sequelae following autologous or allogeneic bone marrow transplantation.
Zarzio is indicated for chronic administration to increase neutrophil counts and to reduce the incidence and duration of infections in patients with severe chronic neutropenia (SCN).
Zarzio is indicated in patients with HIV infection, for reversal of clinically significant neutropenia and subsequent maintenance of adequate neutrophil counts during treatment with antiviral and/or other myelosuppressive medications.

4.2 Dose and Method of Administration

Dosage.

In order to improve the traceability of granulocyte colony stimulating factors (G-CSFs), the trade name of the administered product should be clearly recorded in the patient file.

Cancer patients receiving standard dose cytotoxic chemotherapy or induction/ consolidation chemotherapy for acute myeloid leukaemia.

In adults and children receiving induction/ consolidation chemotherapy for AML, the recommended starting dose is 5 microgram/kg/day administered as a single daily subcutaneous (SC) injection.
In patients with nonmyeloid malignancies receiving standard dose cytotoxic chemotherapy, the recommended starting dose of Zarzio is 5 microgram/kg/day, administered as a single daily SC injection or short IV infusion (over 15 to 30 minutes). In phase 3 trials efficacy was observed at doses of 4 to 8 microgram/kg/day.
Zarzio should not be administered in the period 24 hours before to 24 hours after the administration of chemotherapy (see Section 4.4 Special Warnings and Precautions for Use).
The duration of Zarzio therapy needed to attenuate chemotherapy induced neutropenia may be dependent on the myelosuppressive potential of the chemotherapy regimen employed. In patients with nonmyeloid malignancies receiving standard dose cytotoxic chemotherapy, Zarzio should be administered daily for up to 2 weeks, until the Absolute Neutrophil Count (ANC) has reached 10 x 109/L following the expected chemotherapy induced neutrophil nadir. In patients with AML receiving induction or consolidation chemotherapy, Zarzio should be administered daily until the ANC has reached > 1.0 x 109/L for 3 consecutive days or > 10 x 109/L for 1 day following the expected chemotherapy induced neutrophil nadir.

Patients with nonmyeloid malignancies receiving high dose cytotoxic chemotherapy with autologous or allogeneic bone marrow or peripheral blood progenitor cell transplantation.

The recommended starting dose of Zarzio is 10 microgram/kg/day given by continuous SC infusion or by IV infusion over 4 to 24 hours. Zarzio should be diluted in 25 to 50 mL of 5% glucose solution.
The first dose of Zarzio should be administered not less than 24 hours following cytotoxic chemotherapy and within 24 hours of bone marrow or PBPC infusion.
Once the neutrophil nadir has been passed, the daily dose of Zarzio should be titrated against the neutrophil response as follows. See Table 1.

Patients with myeloid malignancies receiving high dose cytotoxic chemotherapy with autologous or allogeneic bone marrow or peripheral blood progenitor cell transplantation.

Following transplant, the recommended dose of Zarzio to be given to the recipient is 5 microgram/kg/day until neutrophil recovery (up to 28 days).
When given post-transplantation, the first dose of Zarzio should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after infusion of bone marrow or PBPCs.

Autologous peripheral blood progenitor cell collection and therapy.

The recommended dose of Zarzio for PBPC mobilisation when used alone is 10 microgram/kg/day given as a single daily SC injection or a continuous 24 hour infusion. Zarzio therapy should be given for at least 4 days before the first leukapheresis procedure and should be continued through to the day of the last leukapheresis procedure. Collections should be commenced on day 5 and continued on consecutive days until the desired yield of haemopoietic progenitor cells is obtained. For PBPCs mobilised with Zarzio alone, a schedule of leukapheresis collections on days 5, 6 and 7 of a 7 day treatment regimen has been found to be effective. In some patients with extensive prior chemotherapy, additional daily doses of Zarzio may be required to support additional leukaphereses to reach the desired target yield of cells (see Section 4.4 Special Warnings and Precautions for Use, Peripheral blood progenitor cell collection and therapy, Prior exposure to cytotoxic agents).
The recommended dose of Zarzio for PBPC mobilisation after myelosuppressive chemotherapy is 5 microgram/kg/day given daily by SC injection from 24 hours after completion of chemotherapy until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresis should be commenced during the period when the ANC rises from < 0.5 x 109/L to > 5.0 x 109/L. Leukapheresis collection should be repeated on consecutive days until an adequate number of progenitor cells is obtained (see Section 4.4 Special Warnings and Precautions for Use, Peripheral blood progenitor cell collection and therapy, Prior exposure to cytotoxic agents).
In all clinical trials of Zarzio for the mobilisation of PBPCs, filgrastim was administered following infusion of the collected cells. In the randomised phase 3 study, patients received Zarzio 5 microgram/kg/day post-transplantation until a sustainable ANC (> 0.5 x 109/L) was reached (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Peripheral blood progenitor cell collection and therapy).
When given post-transplantation, the first dose of Zarzio should be administered at least 24 hours after cytotoxic chemotherapy and at least 24 hours after infusion of PBPCs.

Allogeneic peripheral blood progenitor cell collection from normal donors.

For PBPC mobilisation in normal donors, Zarzio should be administered at 10 microgram/kg/day SC for 4 to 5 consecutive days. Leukapheresis should be started on day 5 and daily collections continued on day 6 in order to collect a target yield of 4 x 106 CD34+ cells/kg recipient bodyweight.

Patients with severe chronic neutropenia.

Care should be taken to confirm the diagnosis of SCN, which may be difficult to distinguish from myelodysplasia (MDS), before initiating Zarzio therapy.
It is essential that serial Full Blood Counts (FBCs) with differential and platelet counts and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of Zarzio therapy.
Starting dose.

Congenital neutropenia.

The recommended daily starting dose is 12 microgram/kg SC every day (single or divided doses).

Idiopathic or cyclic neutropenia.

The recommended daily starting dose is 5 microgram/kg SC every day (single or divided doses).
Zarzio may be administered SC as a single daily injection to increase and sustain the average neutrophil count above 1.5 x 109/L. Chronic daily administration is required to maintain an adequate neutrophil count.
Dose adjustment. After 1 to 2 weeks of therapy, the initial dose may be doubled or halved. Subsequently, the dose may be individually adjusted not more than every 1 to 2 weeks to maintain the average neutrophil count between 1.5 and 10 x 109/L. The dose should be reduced if the ANC is persistently above 10 x 109/L for 1 to 2 weeks.
In clinical trials, 97% of patients who responded to treatment with Zarzio were treated at doses ≤ 24 microgram/kg/day. In the SCN postmarketing surveillance study, the reported median daily doses of Zarzio were: 6.0 microgram/kg (congenital neutropenia), 2.1 microgram/kg (cyclic neutropenia), and 1.2 microgram/kg (idiopathic neutropenia). In rare instances, patients with congenital neutropenia have required doses of Zarzio ≥ 100 microgram/kg/day.

Patients with HIV infection.

For reversal of neutropenia.

The recommended starting dose of Zarzio is 1 microgram/kg/day administered daily by SC injection with titration up to a maximum of 5 microgram/kg/day until a normal neutrophil count is reached and can be maintained (ANC ≥ 2.0 x 109/L). In clinical studies, 96% of patients responded to filgrastim at these doses, achieving reversal of neutropenia in a median of 2 days.
In a small number of patients (2%), doses of up to 10 microgram/kg/day were required to achieve reversal of neutropenia.

For maintaining neutrophil counts.

When reversal of neutropenia has been achieved, the minimal effective dose of Zarzio to maintain a normal neutrophil count should be established. Initial dose adjustment to 3 times weekly dosing with 300 microgram/day by SC injection is recommended. Further dose adjustment may be necessary, as determined by the patient's ANC, to maintain the neutrophil count at ≥ 2.0 x 109/L. In clinical studies, dosing with 300 microgram/day on 1 to 7 days per week was required to maintain the ANC ≥ 2.0 x 109/L, with the median dose frequency being 3 days per week. Long-term administration may be required to maintain the ANC ≥ 2.0 x 109/L. Zarzio dosing should be reduced and then stopped if myelosuppressive medication is discontinued and there is no recurrence of neutropenia.

Method of administration.

For parenteral administration.

Dilution.

If required, Zarzio may be diluted in 5% glucose. Zarzio diluted to concentrations below 15 microgram/mL should be protected from adsorption to plastic materials by addition of albumin (human) to a final concentration of 2 mg/mL. When diluted in 5% glucose or 5% glucose plus albumin (human), Zarzio is compatible with glass and a variety of plastics including PVC, polyolefin and polypropylene.
Dilution to a final concentration of less than 5 microgram/mL Zarzio is not recommended at any time. Infusion should be complete within 24 hours of the sterile dilution and transfer. (See Section 6.4 Special Precautions for Storage, for details of storage of diluted Zarzio.)
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If particulates or discolouration are observed, the container should not be used.

4.3 Contraindications

Zarzio is contraindicated in patients with known hypersensitivity to E. coli derived products, filgrastim, any of the excipients, or any other component of the product.

4.4 Special Warnings and Precautions for Use

General.

Substitutability.

This product has been shown to be comparable with Neupogen (filgrastim rbe). Substitution should only take place under the supervision of a medical practitioner. The product is not interchangeable by the dispensing pharmacist.

Splenomegaly and splenic rupture.

Splenic rupture has been reported following administration of filgrastim; some of these cases were fatal. Left upper abdominal pain and/or shoulder tip pain accompanied by rapid increase in spleen size should be carefully monitored due to the uncommon (≥ 1/1000 and < 1/100) but serious risk of splenic rupture.

Patients with sickle cell disease.

Clinicians should use caution and monitor patients accordingly when administering filgrastim to patients with sickle cell trait or sickle cell disease because of the reported association of filgrastim with sickle cell crisis (in some cases fatal).
Use of filgrastim in patients with sickle cell disease should be considered only after careful evaluation of the potential risks and benefits.

Thrombocytopenia.

Thrombocytopenia has been reported commonly (≥ 1/100 and < 1/10) in patients receiving filgrastim. Regular monitoring of the platelet count is recommended.

Acute respiratory distress syndrome.

There have been occasional reports of the occurrence of adult respiratory distress syndrome (ARDS) in patients receiving filgrastim. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs, such as cough, fever and dyspnoea in association with radiological signs of lung infiltration and deterioration in pulmonary function may be preliminary signs leading to respiratory failure or ARDS. Filgrastim should be immediately discontinued and appropriate treatment given.

Pulmonary haemorrhage and haemoptysis.

Pulmonary haemorrhage and haemoptysis requiring hospitalisation have been reported in G-CSF-treated healthy donors undergoing peripheral blood progenitor cell (PBPC) collection mobilisation. Haemoptysis resolved with discontinuation of G-CSF.

Glomerulonephritis.

Glomerulonephritis has been reported in patients receiving filgrastim. Generally, after dose reduction or withdrawal of filgrastim, events of glomerulonephritis resolved. Monitoring of urinalysis is recommended.

Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) in patients with breast and lung cancer.

In the post-marketing observational study setting, MDS and AML have been associated with the use of filgrastim in conjunction with chemotherapy and/or radiotherapy in breast and lung cancer patients. Monitor patients for signs and symptoms of MDS/AML in these settings. There has been limited association between the occurrence of MDS and AML and the use of filgrastim in conjunction with chemotherapy and/or radiotherapy in breast cancer patients.

Use in myelodysplasia and leukaemia.

The safety and efficacy of filgrastim administration in patients with MDS or chronic myeloid leukaemia (CML) receiving myelosuppressive chemotherapy without stem cell support have not been established.
Randomised studies of filgrastim in patients undergoing chemotherapy for AML demonstrate no stimulation of disease as measured by remission rate, relapse and survival.

Aortitis.

Aortitis has been reported in patients receiving filgrastim and may present with generalised signs and symptoms such as fever and increased inflammatory markers. Consider aortitis in patients who develop these signs and symptoms without known aetiology.

Capillary leak syndrome.

Capillary leak syndrome has been reported after granulocyte colony stimulating factor administration, and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care (see Section 4.8 Adverse Effects (Undesirable Effects)).

Record of trade name.

In order to improve the traceability of G-CSFs, the trade name of the administered product should be clearly recorded in the patient file.

Cancer patients receiving myelosuppressive chemotherapy.

Concurrent use with chemotherapy and radiotherapy.

The safety and efficacy of filgrastim given concurrently with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, the use of filgrastim is not recommended in the period 24 hours before to 24 hours after the administration of chemotherapy (see Section 4.2 Dose and Method of Administration).
No controlled study has been done to examine the combination of chemoradiotherapy and filgrastim on platelet count in a suitable oncology setting. Therefore, until more definitive data are available, simultaneous use of filgrastim with chemoradiation should be undertaken with caution.

Leukocytosis.

White blood cell (WBC) counts of 100 x 109/L or greater were observed in approximately 2% of patients receiving filgrastim at doses above 5 microgram/kg/day. There were no reports of adverse events associated with this degree of leukocytosis. In order to avoid the potential complications of excessive leukocytosis, a full blood count (FBC) is recommended twice per week during filgrastim therapy (see Section 4.4 Special Warnings and Precautions for Use, Laboratory monitoring, Patients with sickle cell disease).

Premature discontinuation of filgrastim therapy.

A transient increase in neutrophil counts is typically seen 1 to 2 days after initiation of filgrastim therapy. However, for a sustained therapeutic response, filgrastim therapy should be continued until the postnadir ANC reaches 10 x 109/L. Therefore, the premature discontinuation of filgrastim therapy, prior to the time of recovery from the expected neutrophil nadir, is generally not recommended (see Section 4.2 Dose and Method of Administration).

Risks associated with increased doses of chemotherapy.

In studies of filgrastim administration following chemotherapy, most reported side effects were consistent with those usually seen as a result of cytotoxic chemotherapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Because of the potential of receiving higher doses of chemotherapy (i.e. full doses on the prescribed schedule for a longer period), the patient may be at greater risk of thrombocytopenia which should be monitored carefully. Anaemia and nonhaematological consequences of increased chemotherapy doses (please refer to the prescribing information of the specific chemotherapy agents used) also may occur. Regular monitoring of the haematocrit and platelet count is recommended. Furthermore, care should be exercised in the administration of filgrastim in conjunction with drugs known to lower the platelet count and in the presence of moderate or severe organ impairment. Thrombocytopenia may be more severe than normal in later courses of chemotherapy.
The use of filgrastim mobilised PBPCs has been shown to reduce the depth and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.

Peripheral blood progenitor cell collection and therapy.

Mobilisation.

There are no prospectively randomised comparisons of the 2 recommended mobilisation methods (filgrastim alone, or in combination with myelosuppressive chemotherapy) within the same patient population. The degree of variation between both different patient groups and results of laboratory assays of CD34+ cells means that direct comparison between different studies is difficult and an optimum method cannot yet be recommended. The choice of mobilisation method should be considered in relation to the overall objectives of treatment for an individual patient.

Assessment of progenitor cell yields.

In assessing the number of progenitor cells harvested in patients treated with filgrastim, particular attention should be paid to the method of quantitation. The results of flow cytometric analysis of CD34+ cell numbers vary depending on the precise methodology used. Recommendations for minimum acceptable progenitor cell yield based on studies using methods other than that of the reporting laboratory need to be interpreted with caution.
Statistical analysis of the relationship between the number of CD34+ cells infused and the rate of platelet recovery after high dose chemotherapy indicates a complex but continuous relationship, with the probability of more rapid platelet recovery increasing as the CD34+ cell yield increases.
Currently, the minimum acceptable yield of CD34+ cells is not well defined. The recommendation of a minimum yield of ≥ 2 x 106 CD34+ cells/kg is based on published experience resulting in adequate haematologic reconstitution.

Prior exposure to cytotoxic agents.

Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient mobilisation of PBPCs to achieve the recommended minimum yield (≥ 2 x 106 CD34+ cells/kg) or acceleration of platelet recovery, to the same degree. When PBPC transplantation is envisaged it is advisable to plan the stem cell mobilisation procedure early in the treatment course of the patient. Particular attention should be paid to the number of progenitor cells mobilised in such patients before the administration of high dose chemotherapy.
In one phase 2 study in heavily pretreated patients with acute lymphoblastic leukaemia, non-Hodgkin's lymphoma or Hodgkin's disease, no increased yield of progenitor cells was demonstrated by increasing the dose of filgrastim beyond that recommended.
If yields are inadequate, as measured by the criterion above, alternative forms of treatment not requiring progenitor cell support should be considered.
Some cytotoxic agents exhibit particular toxicities to the haemopoietic progenitor pool and may adversely affect progenitor cell mobilisation. Agents such as melphalan, carmustine (BCNU) and carboplatin, when administered over prolonged periods prior to attempts at progenitor cell mobilisation, may reduce progenitor cell yield. Nevertheless, the administration of melphalan, carboplatin or BCNU together with filgrastim has been shown to be effective for progenitor cell mobilisation.

Leukocytosis.

During the period of administration of filgrastim for PBPC mobilisation in cancer patients, discontinuation of filgrastim is appropriate if the leukocyte count rises to > 100 x 109/L. (See Section 4.4 Special Warnings and Precautions for Use, Patients with sickle cell disease.)

Tumour contamination of bone marrow and leukapheresis products.

Some studies of patient bone marrow and leukapheresis products have demonstrated the presence of malignant cells. While the possibility exists for tumor cells to be released from the marrow during mobilisation of PBPCs and subsequently collected in the leukapheresis product, in most of the studies, leukapheresis products appear to be less contaminated than bone marrow from the same patient. The effect of reinfusion of tumor cells has not been well studied and the limited data available are inconclusive.

Normal donors undergoing peripheral blood progenitor cell mobilisation.

Mobilisation of PBPC does not provide a direct clinical benefit to normal donors and should only be considered for the purposes of allogeneic stem cell transplantation.
PBPC mobilisation should be considered only in donors who meet normal clinical and laboratory eligibility criteria for stem cell donation with special attention to haematological values and infectious disease.
The safety and efficacy of filgrastim has not been assessed in normal donors < 16 years or > 60 years.
Transient thrombocytopenia (platelets < 100 x 109/L) following filgrastim administration and leukapheresis was observed in 35% of subjects studied. Among these, 2 cases of platelets < 50 x 109/L were reported and attributed to the leukapheresis procedure.
If more than 1 leukapheresis is required, particular attention should be paid to donors with platelets < 100 x 109/L prior to leukapheresis; in general apheresis should not be performed if platelets are < 75 x 109/L.
Leukapheresis should not be performed in donors who are anticoagulated or who have known defects in haemostasis.
Filgrastim administration should be discontinued or its dosage should be reduced if the leukocyte counts rise to > 100 x 109/L.
Donors who receive filgrastim for PBPC mobilisation should be monitored until haematological indices return to normal.
Insertion of a central venous catheter should be avoided where possible, and therefore consideration should be given to the adequacy of venous access when selecting donors.
Long-term safety follow-up of donors is ongoing. For up to 4 years, there have been no reports of abnormal haematopoiesis in normal donors. 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 to ensure monitoring of long-term safety.
There have been uncommon (≥ 1/1000 and < 1/100) cases of splenic rupture reported in healthy donors following administration of G-CSFs. In donors experiencing left upper abdominal pain and/or shoulder tip pain and rapid increase in spleen size, the risk of splenic rupture should be considered and carefully monitored.
In normal donors, pulmonary adverse events (haemoptysis, lung infiltration) have been reported very rarely (< 1/10,000).

Recipients of allogeneic peripheral blood progenitor stem cells mobilised with filgrastim.

Current data indicate that immunological interactions between the allogeneic PBPC graft and the recipient may be associated with an increased risk of acute and chronic Graft versus Host Disease (GvHD) when compared with bone marrow transplantation.

Patients with severe chronic neutropenia.

Diagnosis of SCN.

Care should be taken to confirm the diagnosis of SCN, which may be difficult to distinguish from MDS, before initiating filgrastim therapy. The safety and efficacy of filgrastim in the treatment of neutropenia or pancytopenia due to other haemopoietic disorders (e.g. myelodysplastic disorders or myeloid leukaemia) have not been established.
It is, therefore, essential that serial FBCs with differential and platelet counts and an evaluation of bone marrow morphology and karyotype be performed prior to initiation of filgrastim therapy. The use of filgrastim prior to diagnostic confirmation of SCN may mask neutropenia as a diagnostic sign of a disease process other than SCN and prevent adequate evaluation and appropriate treatment of the underlying condition causing the neutropenia.

Myelodysplasia and acute myeloid leukaemia.

Cytogenetic abnormalities, transformation to MDS and AML have been observed in patients treated with filgrastim for SCN. Myelodysplasia and AML have been reported to occur in the natural history of SCN without cytokine therapy. Based on available data including a postmarketing surveillance study, the risk of developing MDS and AML appears to be confined to the subset of patients with congenital neutropenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Abnormal cytogenetics have been associated with the development of myeloid leukaemia. The effect of filgrastim on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or MDS, the risks and benefits of continuing filgrastim should be carefully considered.

Patients with HIV infection.

Risks associated with increased doses of myelosuppressive medications.

Treatment with filgrastim alone does not preclude thrombocytopenia and anaemia due to myelosuppressive medications. As a result of the potential to receive higher doses or a greater number of medications with filgrastim therapy, the patient may be at higher risk of developing thrombocytopenia and anaemia. Regular monitoring of blood counts is recommended (see Section 4.4 Special Warnings and Precautions for Use, Laboratory monitoring, Patients with HIV infection).

Infections and malignancies causing myelosuppression.

Neutropenia may also be due to bone marrow infiltrating opportunistic infections such as Mycobacterium avium complex or malignancies such as lymphoma. In patients with known bone marrow infiltrating infection or malignancy, consideration should be given to appropriate therapy for treatment of the underlying condition. The effects of filgrastim on neutropenia due to bone marrow infiltrating infection or malignancy have not been well established.

Laboratory monitoring.

Immunogenicity.

As with all therapeutic proteins, there is potential for immunogenicity. Rates of antibody generation against filgrastim are generally low. Binding antibodies do develop but have not been associated with neutralising activity or adverse clinical consequences. The detection of antibody formation is dependent on the sensitivity and specificity of the assay. The observed incidence of antibody positivity (including neutralising antibody) in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease, therefore comparison of the incidence of antibodies to other products may be misleading.

Cancer patients receiving myelosuppressive chemotherapy.

An FBC, haematocrit and platelet count should be obtained prior to chemotherapy and at regular intervals (twice per week) during filgrastim therapy. Following cytotoxic chemotherapy, the neutrophil nadir occurred earlier during cycles when filgrastim was administered and WBC differentials demonstrated a left shift, including the appearance of promyelocytes and myeloblasts. In addition, the duration of severe neutropenia was reduced and was followed by an accelerated recovery in the neutrophil counts. Therefore, regular monitoring of WBC counts, particularly at the time of the recovery from the postchemotherapy nadir is recommended in order to avoid excessive leukocytosis (see Section 4.2 Dose and Method of Administration).

Peripheral blood progenitor cell collection and therapy.

After 4 days of filgrastim treatment for PBPC mobilisation, neutrophil counts should be monitored. Frequent complete blood counts and platelet counts are recommended following infusion of PBPCs, at least 3 times per week until haemopoietic recovery.
The mobilisation and apheresis procedures should be performed in collaboration with an oncology haematology centre with acceptable experience in this field and where the monitoring of haemopoietic progenitor cells can be appropriately performed and interpreted (see Section 4.4 Special Warnings and Precautions for Use, Peripheral blood progenitor cell collection and therapy).

Patients with severe chronic neutropenia.

During the initial 4 weeks of filgrastim therapy and for 2 weeks following any dose adjustment, an FBC with differential count should be performed twice weekly. Once a patient is clinically stable, an FBC with differential count and platelet determination should be performed monthly during the first year of treatment. Thereafter, if clinically stable, routine monitoring with regular FBCs (i.e. as clinically indicated but at least quarterly) is recommended. Additionally, for those patients with congenital neutropenia, annual bone marrow and cytogenetic evaluations should be performed throughout the duration of treatment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
In clinical trials, the following laboratory results were observed.
Cyclic fluctuations in the neutrophil counts were frequently observed in patients with congenital or idiopathic neutropenia after initiation of filgrastim therapy.
Platelet counts were generally at the upper limits of normal prior to filgrastim therapy. With filgrastim therapy, platelet counts decreased but generally remained within normal limits (see Section 4.8 Adverse Effects (Undesirable Effects)).
Early myeloid forms were noted in peripheral blood in most patients, including the appearance of metamyelocytes and myelocytes. Promyelocytes and myeloblasts were noted in some patients.
Relative increases were occasionally noted in the number of circulating eosinophils and basophils. No consistent increases were observed with filgrastim therapy.

Patients with HIV infection.

Absolute neutrophil count should be monitored closely, especially during the first few weeks of filgrastim therapy. Some patients may respond very rapidly with a considerable increase in neutrophil count after initial doses of filgrastim. It is recommended that the ANC is measured daily for the first 2 to 3 days of filgrastim administration. Thereafter, it is recommended that the ANC is measured at least twice per week for the first 2 weeks and subsequently once per week or once every other week during maintenance therapy. During intermittent dosing with 300 microgram of filgrastim, there will be wide fluctuations in the patient's ANC over time. In order to determine a patient's trough or nadir ANC, it is recommended that blood samples for ANC measurement are obtained immediately prior to any scheduled dosing with filgrastim.

Latex-sensitive individuals.

The needle shield of filgrastim contains a derivative of natural rubber latex. Although no natural rubber latex is detected in the needle shield, the safe use of filgrastim in latex-sensitive individuals has not been studied.

Use in the elderly.

No data available.

Paediatric use.

Long-term follow-up data are available from a postmarketing surveillance study in SCN patients including 32 infants, 200 children and 68 adolescents. The data suggest that height and weight are not adversely affected in paediatric patients who received up to 5 years of filgrastim treatment. Limited data from patients who were followed in a phase 3 study to assess the safety and efficacy of filgrastim in SCN for 1.5 years did not suggest alterations in sexual maturation or endocrine function.
Paediatric patients with congenital types of neutropenia (Kostmann's syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to MDS and AML while receiving chronic filgrastim treatment. The relationship of these events to filgrastim administration is unknown (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
Although use in children with AML is not excluded, published experience is limited and safety has not been clearly established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Bone imaging.

Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.

Lithium.

The potential for pharmacodynamic interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated. There is no evidence that such an interaction would be harmful.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Filgrastim had no observed effect on the fertility of male or female rats, or gestation at doses up to 500 microgram/kg. No human data are available.
(Category B3)
There are no studies of the use of filgrastim in pregnant women. However, there are cases in the literature where the transplacental passage of filgrastim has been demonstrated. Filgrastim should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus.
Reproductive studies in pregnant rats have shown that filgrastim was not associated with lethal, teratogenic or behavioral effects on foetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 microgram/kg/day (see Section 5.3 Preclinical Safety Data, Teratogenicity).
 It is not known whether filgrastim is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised in the use of filgrastim in nursing women.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Cancer patients receiving myelosuppressive chemotherapy.

In clinical trials involving over 200 patients receiving filgrastim following cytotoxic chemotherapy, most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. In all phase 2/3 trials, medullary bone pain was the only consistently observed adverse reaction attributed to filgrastim therapy, reported in 24% of patients. This bone pain was generally reported to be of mild to moderate severity and could be controlled in most patients with non-narcotic analgesics. Infrequently, bone pain was severe enough to require narcotic analgesics. Bone pain was reported more frequently in patients treated with higher doses (20 to 100 microgram/kg/day) administered intravenously and less frequently in patients treated with lower SC doses of filgrastim (3 to 10 microgram/kg/day).
In the randomised, double blind, placebo controlled trial of filgrastim therapy following combination chemotherapy in patients with small cell lung cancer, the following adverse events were reported to be possibly, probably, or definitely related to the double blind study medication (placebo or filgrastim at 4 to 8 microgram/kg/day). (See Table 2.)
In this study, there were no serious, life threatening or fatal adverse reactions attributed to filgrastim therapy. Specifically, there were no reports of flu-like symptoms, pleuritis, pericarditis or other major systemic reactions to filgrastim.
Spontaneously reversible elevations in uric acid, lactate dehydrogenase and alkaline phosphatase occurred in 26% to 56% of patients receiving filgrastim following cytotoxic chemotherapy. These elevations were not reported to be associated with clinical adverse events.
The occurrence of stomatitis and diarrhoea in patients receiving allogeneic transplants is consistent with the use of myeloablative chemotherapy. In a study of 70 patients undergoing allogeneic bone marrow transplantation in which 33 patients were randomised to the placebo group and 37 to the filgrastim group, the incidence and severity of diarrhoea and stomatitis increased from the pre- to the post-transplant period in both the placebo and filgrastim treated patients. Prior to transplantation, 12 patients randomised to the placebo group and 6 patients randomised to filgrastim reported moderate to severe diarrhoea. Following transplantation, the incidence of moderate to severe diarrhoea increased to 23 and 14 patients respectively. No patients in either group experienced moderate or severe stomatitis prior to transplantation, while after transplantation, 19 patients in the placebo group and 8 patients in the filgrastim group reported moderate to severe stomatitis.
In a randomised, double blind, placebo controlled phase 3 study of patients with AML, there were 3 patients reported to have developed ARDS during the study (2 filgrastim, 1 placebo). This is a rare but expected event in this patient population, and all 3 patients had recognised predisposing factors. As a causal relationship between the development of ARDS and filgrastim treatment has not been established, and as multiple risk factors are often present, any decision to discontinue filgrastim in this setting should be based on the overall assessment of contributing factors.
Capillary leak syndrome, which can be life threatening if treatment is delayed, has been reported uncommonly (≥ 1/1000 to < 1/100) in cancer patients undergoing chemotherapy and healthy donors undergoing peripheral blood progenitor cell mobilisation following administration of granulocyte colony stimulating factor. (See Section 4.4 Special Warnings and Precautions for Use.)
Rare cases (≤ 1/10,000 to and < 1/1,000) of Sweet's syndrome (acute febrile neutrophilic dermatosis) have been reported.
Very rare (estimated 0.03 cases per 100,000 exposures [0.00003%]) events of chondrocalcinosis pyrophosphate have been reported in patients with cancer treated with filgrastim.

Chronic administration.

With chronic administration, clinical splenomegaly has been reported in 30% of patients. Less frequently observed adverse events included exacerbation of some pre-existing skin disorders (e.g. psoriasis), cutaneous vasculitis (leukocytoclastic), alopecia, haematuria/ proteinuria, thrombocytopenia (platelets < 50 x 109/L) and osteoporosis. Patients receiving chronic treatment with filgrastim should be monitored periodically for the appearance of these conditions.
No evidence of interaction of filgrastim with other drugs was observed in the course of clinical trials (see Section 4.4 Special Warnings and Precautions for Use, Concurrent use with chemotherapy and radiotherapy). Since commercial introduction of filgrastim there have been rare reports (< 1 in 100,000 administrations) of symptoms suggestive of allergic type reactions such as anaphylaxis, dyspnoea, hypotension, skin rash, and urticaria, but in which an immune component has not been demonstrated. Approximately half occurred following the initial dose; reactions occurred more frequently with IV administration. Symptoms recurred in some patients rechallenged. There have been rare reports (< 1 in 500,000 administrations) of cutaneous vasculitis. Filgrastim should be permanently discontinued in patients who experience a serious allergic reaction.
In chronically treated patients, including some who have received filgrastim daily for almost 2 years, there has been no evidence of the development of antibodies to filgrastim or a blunted or diminished response over time.

Peripheral blood progenitor cell collection and therapy.

Filgrastim mobilised autologous PBPC collection.

In clinical trials, 126 patients have received filgrastim for mobilisation of PBPCs. During the mobilisation period, adverse events related to filgrastim consisted primarily of mild to moderate musculoskeletal symptoms, reported in 44% of patients. These symptoms were predominantly events of medullary bone pain (38%). Headache was reported related to filgrastim in 7% of patients. Mild to moderate transient increases in alkaline phosphatase levels were reported related to filgrastim in 21% of the patients who had serum chemistries evaluated during the mobilisation phase.
All patients had increases in neutrophil counts consistent with the biological effects of filgrastim. Two patients had a WBC count greater than 100 x 109/L with WBC count increases during the mobilisation period ranging from 16.7 to 138 x 109/L above baseline. Eighty eight percent of patients had an increase in WBC count between 10 and 70 x 109/L above baseline. No clinical sequelae were associated with any grade of leukocytosis.
Sixty five percent of patients had downward shifts in haemoglobin, which were generally mild to moderate (59%) and 97% of patients had decreases in platelet counts related to the leukapheresis procedure. Only 2 patients had platelet counts less than 50 x 109/L.

Allogeneic peripheral blood progenitor cell mobilisation in normal donors.

The most commonly reported adverse event was mild to moderate transient musculoskeletal pain. Leukocytosis (WBC > 50 x 109/L) was observed in 41% of donors and transient thrombocytopenia (platelets < 100 x 109/L) following filgrastim and leukapheresis was observed in 35% of donors.
Transient, minor increases in alkaline phosphatase, LDH, AST and uric acid have been reported in normal donors receiving filgrastim; these were without clinical sequelae.
Exacerbation of arthritic symptoms has been observed very rarely.
Symptoms suggestive of severe allergic reactions have been reported very rarely.
Headaches, believed to be caused by filgrastim, have been reported in PBPC donor studies.
There have been uncommon (≥ 1/1000 and < 1/100) cases of splenic rupture reported in normal donors receiving G-CSFs (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon (≥ 1/1000 and < 1/100) cases of capillary leak syndrome have been reported.
In normal donors, pulmonary adverse events (haemoptysis, pulmonary infiltrates) have been reported very rarely (< 0.01%).

PBPC transplantation supported by filgrastim.

During the period of filgrastim administration postinfusion of autologous PBPCs, filgrastim was administered to 110 patients as supportive therapy and adverse events were consistent with those expected after high dose chemotherapy. Mild to moderate musculoskeletal pain was the most frequently reported adverse event related to filgrastim, reported in 15% of patients. In patients receiving allogeneic PBPCs, a similar incidence of musculoskeletal pain was reported.

Patients with severe chronic neutropenia.

The safety and efficacy of chronic daily administration of filgrastim in patients with SCN have been established in phase 1/2 clinical trials of 74 patients treated for up to 3 years and in a phase 3 trial of 123 patients treated for up to 2 years.
Mild to moderate bone pain was reported in approximately 33% of patients in clinical trials. This symptom was readily controlled with mild analgesics. General musculoskeletal pain was also noted in higher frequency in patients treated with filgrastim. Palpable splenomegaly was observed in approximately 30% of patients. Abdominal or flank pain was seen infrequently and thrombocytopenia (< 50 x 109/L) was noted in 12% of patients with palpable spleens. Less than 3% of all patients underwent splenectomy and most of these had a prestudy history of splenomegaly. Less than 6% of patients had thrombocytopenia (< 50 x 109/L) during filgrastim therapy, most of whom had a prestudy history. In most cases, thrombocytopenia was managed by filgrastim dose reduction or interruption.
There were no associated serious haemorrhagic sequelae in these patients. Epistaxis was noted in 15% of patients treated with filgrastim but was associated with thrombocytopenia in 2% of patients. Anaemia was reported in approximately 10% of patients, but in most cases appeared to be related to frequent diagnostic phlebotomy, chronic illness or concomitant medications.
Cytogenetic abnormalities, transformation to MDS and AML have been observed in patients treated with filgrastim for SCN (see Section 4.4 Special Warnings and Precautions for Use, Patients with severe chronic neutropenia, Paediatric use). Based on analysis of data from a postmarketing surveillance study of 531 SCN patients with an average follow-up of 4.0 years, the risk of developing these abnormalities (cytogenetic abnormalities, MDS and AML) appears to be confined to the subset of patients with congenital neutropenia. A life table analysis of these data revealed that the cumulative risk of developing leukaemia or MDS by the end of the 8th year of filgrastim treatment in a patient with congenital neutropenia was 16.5% which is an annual rate of approximately 2%.
Cytogenetic abnormalities, including monosomy 7, have been reported in patients treated with filgrastim who had previously documented normal cytogenetic evaluations. It is unknown whether the development of cytogenetic abnormalities, MDS or AML is related to chronic daily filgrastim administration or to the natural history of SCN. It is also unknown if the rate of conversion in patients who have not received filgrastim is different from that of patients who have received filgrastim. Routine monitoring through regular FBCs is recommended for all SCN patients. Additionally, annual bone marrow and cytogenetic evaluations are recommended in all patients with congenital neutropenia (see Section 4.4 Special Warnings and Precautions for Use, Laboratory monitoring).
Other adverse events infrequently observed and possibly related to filgrastim therapy were: injection site reaction, headache, hepatomegaly, arthralgia, osteoporosis, rash, alopecia, cutaneous vasculitis and haematuria/ proteinuria. Patients receiving chronic treatment with filgrastim should be monitored periodically for the appearance of these conditions.
In postmarketing experience, common cases of decreased bone density and osteoporosis have been reported in paediatric patients with SCN receiving chronic treatment with filgrastim.

Patients with HIV infection.

In 3 clinical studies involving a total of 244 HIV positive patients, the only adverse events that were consistently considered related to filgrastim administration were musculoskeletal pain, predominantly mild to moderate bone pain and myalgia. In the largest of the 3 studies involving 200 patients, the event rate was 12%. This is consistent with the 14% incidence of musculoskeletal pain reported in clinical trials in other indications where doses of 0.35 to 11.5 microgram/kg/day were used. The incidence of severe musculoskeletal pain (3%) was identical to that reported in clinical trials in other indications.
In a small study of 24 patients, there were 7 reports of treatment related splenomegaly, but in a larger study of 200 patients, there were no such reports. In the former study, no baseline measurements of spleen size were made for comparison with on study measurements. In all cases, splenomegaly was mild or moderate on physical examination and the clinical course was benign; no patients had a diagnosis of hypersplenism and no patients underwent splenectomy. As splenic enlargement is a common finding in patients with HIV infection and is present to varying degrees in most patients with AIDS, the relationship to filgrastim treatment is unclear.
An analysis was performed on viral load data, as measured by HIV-1 RNA polymerase chain reaction (PCR), from a controlled randomised study of filgrastim for the prevention of grade 4 neutropenia. No clinically or statistically significant differences were seen between filgrastim treated groups and untreated groups for changes in viral load over a 24 week period. However, since the study was not powered to show equivalence between the groups, the possibility that filgrastim affects HIV-1 replication cannot be excluded. There was also no detrimental effect on immunological markers, which is important in a population of patients in whom a decline in CD4+ T-lymphocyte count is expected. There were no safety concerns with long-term administration of filgrastim in this setting.

Adverse reactions relevant to all indications.

Adverse reactions from combined clinical trial data are listed below. Adverse reactions observed in the combined clinical trial data, which are present in the adverse effects sections by indication above, are not included in this list:
Very common (≥ 1/10) nausea, vomiting, pyrexia, fatigue, and headache.
Common (≥ 1/100 and < 1/10) hypertension, pain, oral pain, oropharyngeal pain, haemoptysis, chest pain, back pain, arthralgia, asthenia, malaise, cough, oedema peripheral, decreased appetite, constipation, sepsis, bronchitis, upper respiratory tract infection, urinary tract infection, muscle spasms, dizziness, hypoaesthesia, paraesthesia, insomnia, erythema and transfusion reaction.
Uncommon (≥ 1/1000 and < 1/100) hypersensitivity, lung infiltration and rash maculo-papular.
Rare (≥ 1/10,000 and < 1/1,000) glomerulonephritis, extramedullary haematopoiesis.

Postmarketing experience relevant to all indications.

Cases of splenomegaly have been reported commonly (≥ 1/100 and < 1/10) in patients treated with filgrastim.
Cases of splenic rupture, sickle cell anaemia with crisis and glomerulonephritis have been reported uncommonly (≥ 1/1000 and < 1/100) in patients treated with filgrastim.
Cases of pulmonary haemorrhage, pulmonary infiltrates, and haemoptysis have been reported in patients receiving filgrastim.
Cases of aortitis have been reported in patients receiving filgrastim.
Cases of myelodysplastic syndrome and acute myeloid leukaemia have been reported in breast and lung cancer patients receiving filgrastim in conjunction with chemotherapy and/or radiotherapy.
Cases of extramedullary haematopoiesis have been reported rarely (≥ 1/10,000 and < 1/1,000) in patients receiving filgrastim.
Cases of capillary leak syndrome have been reported in the postmarketing experience with granulocyte colony stimulating factor use. These have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy medications or undergoing apheresis. (See Section 4.4 Special Warnings and Precautions for Use.)

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

The maximum tolerated dose of filgrastim has not been determined. Twenty seven patients have been treated at filgrastim doses of ≥ 69 microgram/kg/day. Of those, 6 patients have been treated at 115 microgram/kg/day with no toxic effects attributable to filgrastim. Efficacy has been demonstrated using much lower doses (doses of 4 to 8 microgram/kg/day showed efficacy in the phase 3 study). Doses of filgrastim which increase the ANC beyond 10 x 109/L may not result in any additional clinical benefit.
In clinical trials of filgrastim in cancer patients receiving myelosuppressive chemotherapy, WBC counts > 100 x 109/L have been reported in less than 5% of patients, but were not associated with any reported adverse clinical effects.
It is recommended, to avoid the potential risks of excessive leukocytosis, that filgrastim therapy should be discontinued if the ANC surpasses 10 x 109/L after the chemotherapy induced ANC nadir has occurred.
In cancer patients receiving myelosuppressive chemotherapy, discontinuation of filgrastim therapy usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to pretreatment levels in 1 to 7 days.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Colony stimulating factors.

Colony stimulating factors are glycoproteins which act on haemopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment and some end cell functional activation.
Endogenous filgrastim (i.e. granulocyte colony stimulating factor) is a lineage specific colony stimulating factor with selectivity for the neutrophil lineage. Filgrastim is not species specific and has been shown to primarily affect neutrophil progenitor proliferation, differentiation and selected end cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing and the increased expression of some functions associated with cell surface antigens).

Preclinical studies.

The results of all preclinical studies indicate that the pharmacologic effects of filgrastim are consistent with its predominant role as a regulator of neutrophil production and function.

Comparability of Zarzio with Neupogen.

The effects of Zarzio and Neupogen on absolute neutrophil count (ANC) were comparable in healthy volunteers following 1, 2.5 and 5 microgram/kg SC in randomised, double blind, crossover studies (see Tables 3, 4 and 5). Effects on ANC were also comparable following a single 5 microgram/kg intravenous (IV) dose and 10 microgram/kg/day subcutaneous (SC) for 7 days in secondary studies. Effects on CD34+ cells were comparable after 2.5 and 5 microgram/kg SC (see Tables 3 and 4).
Anti-rhG-CSF antibodies were assessed at baseline and at a follow-up visit after dosing but not detected in any of the healthy subjects participating in the Phase I trials.

Clinical trials.

Cancer patients receiving myelosuppressive chemotherapy.

In all clinical studies, administration of filgrastim resulted in a dose dependent rise in neutrophil counts. Following termination of filgrastim therapy, circulating neutrophil counts declined by 50% within 1 to 2 days and to pretreatment levels within 1 to 7 days. Isolated neutrophils displayed normal phagocytic and chemotactic activity in vitro.
In a study of the effects of filgrastim in patients with carcinoma of the urothelium, repeated daily IV dosing with filgrastim resulted in a linear dose dependent increase in circulating neutrophil counts over the dose range of 1 to 70 microgram/kg/day. The effects of filgrastim therapy reversed within 24 hours of the termination of administration and neutrophil counts returned to baseline, in most cases, within 4 days.
In a phase 1 study of patients with a variety of malignancies, including lymphoma, multiple myeloma and adenocarcinoma of the lung, breast and colon, filgrastim induced a dose dependent increase in neutrophil counts. This increase in neutrophil counts was observed whether filgrastim was administered intravenously (1 to 70 microgram/kg twice daily), subcutaneously (1 to 3 microgram/kg once daily) or by continuous SC infusion (3 to 11 microgram/kg/day).
These results were consistent with a phase 1 study of patients with small cell lung cancer who were administered filgrastim prior to chemotherapy. All patients responded to filgrastim (1 to 45 microgram/kg/day), given for 5 days, with a dose dependent increase in median neutrophil count from a baseline of 9.5 x 109/L to a maximum response of 43 x 109/L.
In a randomised, double blind, placebo controlled phase 3 study of small cell lung cancer patients receiving combination chemotherapy (cyclophosphamide, doxorubicin and etoposide), treatment with filgrastim resulted in clinically and statistically significant reductions in both the incidence and duration of infection, as manifested by febrile neutropenia. The incidence, severity and duration of severe neutropenia (ANC < 0.5 x 109/L) following chemotherapy were all significantly reduced, as were the requirements for in patient hospitalisation and antibiotic use (see Section 4.8 Adverse Effects (Undesirable Effects)). With other myelosuppressive regimens (e.g. M-VAC, melphalan), a dose dependent increase in neutrophil counts was observed, as well as a decrease in the duration of severe neutropenia.
In a randomised, double blind, placebo controlled phase 3 study of patients with AML, the median duration of neutropenia (ANC < 0.5 x 109/L) during the first induction cycle was significantly reduced, from 19 days in the placebo group to 14 days in the filgrastim group. The duration of hospitalisation during induction therapy was also significantly reduced in the filgrastim group, from 29 days to 23 days, as were the duration of fever and incidence of IV antibiotic use. Filgrastim had a similar impact on the durations of neutropenia, hospitalisation, fever and IV antibiotic use in subsequent cycles of chemotherapy.
The absolute monocyte count was reported to increase in a dose dependent manner in most patients receiving filgrastim. The percentage of monocytes in the differential count was within the normal range. In all studies to date, absolute counts of both eosinophils and basophils were within the normal range following administration of filgrastim. Small nondose dependent increases in lymphocyte counts following filgrastim administration have been reported in normal subjects and cancer patients.

Peripheral blood progenitor cell (PBPC) collection and therapy.

Use of filgrastim, either alone, or after chemotherapy, mobilises haemopoietic progenitor cells into the peripheral blood. These peripheral blood progenitor cells (PBPCs) may be harvested and infused after high dose chemotherapy, either in place of, or in addition to bone marrow transplantation. Infusion of PBPCs accelerates the rate of neutrophil and platelet recovery reducing the risk of haemorrhagic complications and the need for platelet transfusions.
In a randomised phase 3 study of patients with Hodgkin's disease or non-Hodgkin's lymphoma undergoing myeloablative chemotherapy, 27 patients received autologous filgrastim mobilised peripheral blood progenitor cell transplantation (PBPCT) followed by filgrastim 5 microgram/kg/day and 31 patients received autologous bone marrow transplantation (ABMT) followed by filgrastim 5 microgram/kg/day. Patients randomised to the filgrastim mobilised PBPCT group compared to the ABMT group had significantly fewer median days of platelet transfusions (6 vs. 10 days), a significantly shorter median time to a sustained platelet count > 20 x 109/L (16 vs. 23 days), a significantly shorter median time to recovery of a sustained ANC ≥ 0.5 x 109/L (11 vs. 14 days) and a significantly shorter duration of hospitalisation (17 vs. 23 days).
In all clinical trials of filgrastim for the mobilisation of PBPCs, filgrastim (5 to 24 microgram/kg/day) was administered following infusion of the cells until a sustainable ANC (≥ 0.5 x 109/L) was reached.
Overall, infusion of filgrastim mobilised PBPCs, supported by filgrastim post-transplantation, provided rapid and sustained haematologic recovery. Long-term (approximately 100 days) follow-up haematology data from patients treated with autologous PBPCT alone or in combination with bone marrow was compared to historical data from patients treated with ABMT alone. This retrospective analysis indicated that engraftment is durable.
In a randomised trial comparing filgrastim mobilised allogeneic PBPCT with allogeneic BMT in patients with acute leukaemia, chronic myelogenous leukaemia or myelodysplastic syndrome, filgrastim was given at 10 microgram/kg/day to 163 healthy volunteers for 4 to 5 days followed by leukapheresis beginning on day 5. Another 166 healthy volunteers donated bone marrow. The number of CD34+ cells in the leukapheresis product was generally sufficient to support a transplant, with over 80% of donors achieving the target yield of 4 x 106/kg recipient bodyweight. In the vast majority of donors (95%) sufficient PBPCs (2 x 106 CD34+ cells/kg of recipient) were obtained in ≤ 2 leukaphereses. The median number of CD34+ cells in the leukapheresis product (5.8 x 106/kg) was higher than that of bone marrow product (2.7 x 106/kg); however, the product from both procedures was sufficient to allow each recipient to receive a transplant. Following transplant, all recipients received filgrastim at 5 microgram/kg/day until neutrophil recovery (up to 28 days). Recipients of allogeneic PBPC had a shorter median time to platelet recovery of ≥ 20 x 109/L (15 vs. 20 days) and shorter median time to ANC recovery of ≥ 0.5 x 109/L (12 vs. 15 days). There was no difference in leukaemia free survival at a median follow-up of 12 months.

Patients with severe chronic neutropenia (SCN).

In a randomised, controlled, open label phase 3 trial of 123 patients with idiopathic, cyclic and congenital neutropenia, untreated patients had a median ANC of 0.21 x 109/L. Filgrastim therapy was adjusted to maintain the median ANC between 1.5 and 10 x 109/L. A complete response was seen in 88% of patients (defined as a median ANC ≥ 1.5 x 109/L) over 5 months of filgrastim therapy. Overall, the response to filgrastim therapy for all patients was observed in 1 to 2 weeks. The median ANC after 5 months of filgrastim therapy for all patients was 7.46 x 109/L (range 0.03 to 30.88 x 109/L). In general, patients with congenital neutropenia responded to filgrastim therapy with lower median ANC than patients with idiopathic or cyclic neutropenia.
Overall, daily treatment with filgrastim resulted in clinically and statistically significant reductions in the incidence and duration of fever, infections and oropharyngeal ulcers. As a result, there also were substantial decreases in requirements for antibiotic use and hospitalisation. Additionally, patients treated with filgrastim reported fewer episodes of diarrhoea, nausea, fatigue and sore throat.

Patients with HIV infection.

In an open label, noncomparative study involving 200 HIV positive patients with neutropenia (ANC < 1.0 x 109/L), filgrastim reversed the neutropenia in 98% of patients (ANC ≥ 2.0 x 109/L) with a median time to reversal of 2 days (range 1 to 16) and a median dose of 1 microgram/kg/day (range 0.5 to 10). Ninety six percent of patients achieved reversal of neutropenia with a dose of ≤ 300 microgram/day. Normal ANCs were then maintained with a median dose frequency of 3 times 300 microgram vials/week (range 1 to 7). Ganciclovir, zidovudine, cotrimoxazole and pyrimethamine were the medications most frequently considered to be causing neutropenia and 83% of patients received 1 or more of these on study. During the study, 84% of these patients were able to increase or maintain dosing of these 4 medications or add them to their therapy. The number of these 4 medications received per patient increased by more than 20% (from 0.98 to 1.18) during filgrastim therapy. The median duration of filgrastim treatment was 191 days (range 2 to 815). One hundred fifty three patients received long-term maintenance therapy (> 58 days) and the frequency of dosing was similar to that in the first 30 days of maintenance therapy (71% of patients were receiving 2 to 3 vials per week).
Overall, in patients with HIV infection filgrastim rapidly reverses neutropenia and is subsequently able to maintain normal neutrophil counts during chronic administration.

Comparability of Zarzio with Neupogen.

The efficacy of Zarzio in the prophylaxis of severe neutropenia was demonstrated in patients with breast cancer being treated with chemotherapy in a single arm trial (EP06-301). The patients were Caucasian woman of median age 52 years, range 24-78 years. The chemotherapy was doxorubicin 60 mg/m2 IV and docetaxel 75 mg/m2 IV on day 1 each 3 weeks for 4 cycles. Zarzio was given from day 2 of each cycle for up to 14 days or until ANC reached 10 x 109/L. The dose was 300 microgram/day (weight < 60 kg) or 480 microgram/day (weight ≥ 60 kg) administered SC. The mean dose of Zarzio was 6.1 microgram/kg/day, range 3.7-8.4 microgram/kg/day and the mean exposure 31 days, range 6-48 days.
The incidence and duration of severe neutropenia for each cycle are shown in Table 6. The mean ± sd time to ANC nadir in cycle 1 was 6.3 ± 0.7. The incidence of febrile neutropenia (ANC ≤ 0.5 x 109/L and body temp ≥ 38.2°C) was 7.6% in cycle 1 and 8.2% across all cycles, and the incidence of infections 2.4% in cycle 1 and 8.8% across all cycles. The Zarzio results were comparable to available data for Neupogen in a similar population.
Based on the available data, the safety profiles of Zarzio and Neupogen are comparable.

5.2 Pharmacokinetic Properties

In normal volunteers, serum filgrastim concentrations declined monoexponentially following a single intravenous (IV) infusion, exhibiting a half-life of approximately 3 hours. Clearance and volume of distribution averaged 0.6 mL/minute/kg and 163 mL/kg. Following a single SC injection, peak serum concentrations of filgrastim occurred at approximately 4 to 6 hours. The absorption phase can be fitted to either a zero order or a first order model whereas the elimination phase observed a monoexponential decline. No difference in half-lives were observed following IV and SC doses. The bioavailability was estimated to be approximately 50% following SC administration.
In cancer patients, clearance and volume of distribution of filgrastim were found to be lower than in normal volunteers, averaging approximately 0.12 to 0.34 mL/minute/kg and 56 to 127 mL/kg, respectively. However, the elimination half-life appeared to be similar when compared to normal volunteers, averaging 3 to 4 hours.
Following a single SC injection of 3.45 microgram/kg and 11.5 microgram/kg, peak serum concentrations occurred at approximately 4 to 5 hours and averaged 4 nanogram/mL and 49 nanogram/mL. Continuous SC infusions of 23 microgram/kg of filgrastim over 24 hours in cancer patients resulted in a steady-state concentration of approximately 50 (30 to 70) nanogram/mL. No evidence of drug accumulation was observed over 11 to 20 days of continuous infusion. When a single IV dose (1.73 to 69 microgram/kg) was administered to cancer patients, the area under the serum concentration time curves increased proportional to the dose. Serum concentrations of filgrastim were found to decrease in paediatric cancer patients who were dosed at 5 to 15 microgram/kg/day for 10 days. The decrease of serum concentrations may be associated with a change in the clearance of filgrastim due to increasing neutrophil counts.
Subcutaneous injections of filgrastim solutions containing either sorbitol or mannitol resulted in similar pharmacokinetic profiles and response in ANC. When a single 5 microgram/kg SC dose was administered to normal subjects using 3 concentrations of filgrastim solution (300, 600 and 960 microgram/mL), the 3 concentrations were found to be equivalent in elevating ANC. Although increased maximum serum concentration and area under the serum concentration curve were observed with increasing filgrastim concentrations, these pharmacokinetic differences did not correlate with biological response.

Comparability of Zarzio with Neupogen.

The pharmacokinetic profiles of Zarzio and Neupogen were comparable in healthy volunteers following IV and SC administration in randomised, double blind, crossover studies (see Tables 7 and 8).

5.3 Preclinical Safety Data

Cell proliferation potential.

As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro, and similar effects may be seen on some non-myeloid cells in vitro.

Genotoxicity.

In either the presence or absence of a drug enzyme metabolising system, filgrastim failed to induce chromosomal aberrations (in Chinese hamster lung cells in vitro) or bacterial gene mutations. Filgrastim was negative in an in vivo mouse micronucleus test. Filgrastim failed to induce bacterial gene mutations in either the presence or absence of a drug metabolising enzyme system.

Carcinogenicity.

The carcinogenic potential of filgrastim has not been studied.

Teratogenicity.

The administration of filgrastim to pregnant rabbits during the period of organogenesis at doses of 20 microgram/kg/day IV or greater was associated with an increased incidence of embryonic loss, urogenital bleeding and decreased food consumption. External abnormalities were not observed in the foetuses of treated does, but there was a significant increase in the incidence of fusion of sternebrae at an 80 microgram/kg/day dose. The administration of filgrastim to pregnant rabbits at a dose of 5 microgram/kg/day IV was not associated with observable adverse effects to the doe or foetus (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

6 Pharmaceutical Particulars

6.1 List of Excipients

The pre-filled syringes contain glutamic acid, sorbitol, polysorbate 80, sodium hydroxide (for pH adjustment), and water for injections.
Zarzio bulk solution contains 1.5-2.5 mg/mL rh G-CSF, 10 mM glutamic acid, 5% sorbitol, adjusted to pH 4.4 with sodium hydroxide.

6.2 Incompatibilities

Do not dilute with saline at any time; product may precipitate.

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.

6.4 Special Precautions for Storage

Zarzio should be stored in a refrigerator at 2°-8°C (protected from light).
A single period of exposure to room temperature (25°C) for up to 8 days, does not adversely affect the stability of filgrastim.
Avoid vigorous shaking.
To reduce microbiological hazard, the solution should be administered as soon as practicable after dilution. If storage is necessary, hold at 2°-8°C for a total time not more than 24 hours after dilution.
Prior to injection, Zarzio may be allowed to reach room temperature.

6.5 Nature and Contents of Container

Zarzio 300 microgram/0.5 mL and 480 microgram/0.5 mL prefilled syringe are available in pack of 1, 5 and 10.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

Filgrastim is for single use in one patient only. Discard any residue.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Zarzio is a 175 amino acid protein manufactured by recombinant DNA technology.
It is produced by Escherichia coli bacteria into which has been inserted the human granulocyte colony stimulating factor gene. It has a molecular weight of 18,800 daltons. Zarzio is unglycosylated and contains an N-terminal methionine necessary for expression in E. coli.
The specific activity of filgrastim by in vitro proliferative cell assay is 1 x 108 IU/mg when assayed against the WHO international standard for granulocyte colony stimulating factor, 88/502. The clinical significance of this in vitro potency assignment is unknown.
The chemical name of filgrastim (rbe) is N-(L-Methionyl) granulocyte colony-stimulating factor; recombinant methionylated human Granulocyte Colony-Stimulating Factor.
Amino acid structure (primary sequence) of r-metHuG-CSF:

CAS number.

121181-53-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes