Consumer medicine information

Nivestim

Filgrastim

BRAND INFORMATION

Brand name

Nivestim

Active ingredient

Filgrastim

Schedule

What is in this leaflet

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

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

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

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

What Nivestim is used for

Nivestim - also known as Filgrastim (rbe) - is a copy of a substance normally present in your body, called Granulocyte Colony Stimulating Factor or G-CSF. Using gene technology, Nivestim 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.

This medicine may have been prescribed for you for one of the following reasons:

You are receiving chemotherapy for cancer
Some chemotherapy will reduce the number of white blood cells in your body. Although Nivestim is not a treatment for cancer, it does help the body to make new neutrophils and this will reduce your chance of developing infections that might require antibiotics and/or hospital stays. It may even increase your chance of receiving your chemotherapy on time and at the right dose.
You are receiving a bone marrow transplant or a stem cell transplant
Blood cells are produced in the bone marrow and arise from special ‘parent’ cells, called stem cells. Some chemotherapy has toxic effects on bone marrow, so your doctor may choose to collect stem cells from your bone marrow or blood – or from a donor’s bone marrow or blood – before you receive your chemotherapy. These collected stem cells are then stored and may be given back to you later, to replace those lost during chemotherapy. This procedure is called a bone marrow or stem cell transplant.
There are normally only a small number of stem cells in your blood; Nivestim is typically used to increase this number before stem cell collection. You may also receive Nivestim after a bone marrow or stem cell transplant, to help speed up your recovery.
You are donating stem cells for another person
If you are aged between 16 and 60 years and have volunteered to donate your stem cells for another person, Nivestim may be used to increase the number of stem cells in your blood before they are collected. Your stem cells can then be given to a patient after he/ she has received their chemotherapy.
You are suffering from severe chronic neutropenia
Severe chronic neutropenia is a disease in which the body does not make enough neutrophils, increasing your risk of fever and/ or infection. Nivestim helps the body to make and maintain the right number of infection-fighting neutrophils, decreasing the risk of infection and the need for antibiotics and/or hospital stays.
You are receiving medicines for HIV infection
Some medicines used to treat HIV (Human Immuno-deficiency Virus) infection, or its complications, can reduce the number of infection-fighting neutrophils in your blood. Your doctor may prescribe Nivestim if the number of neutrophils falls too low.
By boosting your neutrophil count, Nivestim will improve your body’s ability to fight infection and may increase your chance of receiving the full dose of some of your HIV medicines. Nivestim is not a treatment for HIV infection.

Ask your doctor if you have any questions about why Nivestim has been prescribed for you

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

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

Before you use Nivestim

When you must not use it

Do not use Nivestim if you have an allergy to:

filgrastim, or any of the ingredients listed at the back of this leaflet
medicines or any other products that are produced by DNA technology using the bacteria E. coli.

Some of the symptoms of an allergic reaction may include:

shortness of breath, wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not use Nivestim at the same time as your chemotherapy or radiotherapy.

Do not use Nivestim in the 24 hours before or the 24 hours after you receive your chemotherapy, radiotherapy, bone marrow transplant or stem cell transplant.

Do not use Nivestim after the expiry date (EXP) printed on the pack or if the packaging is torn or shows signs of tampering.

Do not use Nivestim if it has been left out of the refrigerator for more than fifteen (15) days, or if it has been in the freezer for more than 24 hours, or if it has been frozen more than once.

If you are not sure whether you should use Nivestim, talk to your doctor or pharmacist.

Before you start to use Nivestim

Tell your doctor if you have any allergies to:

any other medicines
any other substances such as foods, preservatives, or dyes.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding or plan to breast feed. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you:

have a medical condition affecting the bone marrow or blood
have a family history of a genetic disorder
suffer from sickle cell disease
have problems with your kidneys, liver, heart or other organs
have had previous treatment for cancer
have any infections, cancers or tumours.
have a recent history of pneumonia (or other serious lung infections).

If you have not told your doctor about any of these things, tell him/her before you use any Nivestim.

Your doctor will decide whether it is safe for you to use Nivestim.

Taking other medicines

Tell your doctor if you are taking any other medicines, particularly those that may affect the blood. Also tell him/her about those you buy without a prescription from a pharmacy, supermarket or health food shop.

Driving and using machinery

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

How to use Nivestim

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

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

Nivestim is given by injection, usually into the tissues just below the skin. This is called a subcutaneous injection and it is a simple procedure.

Your doctor, nurse or pharmacist may suggest that you or your carer be taught how to give a subcutaneous injection. This will allow you to have your Nivestim injection at home.

Nivestim is sometimes given by injection into a vein. This is called an intravenous injection and is generally given by a doctor or nurse.

How much to inject

Your doctor will tell you the strength of Nivestim you need and how much you require. How much you need will depend on the reason for your treatment, your body weight and the number of neutrophils in your blood.

For Nivestim to work properly, you have to use it exactly as your doctor has instructed.

Where to inject

The best injection sites are:

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

The sites are shown in the picture below.

You should change the site of injection each time you inject, to avoid soreness at one site.

When to inject

For the best effect you should inject Nivestim at about the same time each day. Your doctor will tell you when to begin your treatment and when to stop.

How long to use it

Patients receiving chemotherapy or who have received a bone marrow or stem cell transplant are only required to use Nivestim for short periods of time until the number of infection-fighting neutrophils are restored (usually 1 to 3 weeks).

Stem cell donors should receive Nivestim treatment for 4 to 5 days.

Patients with severe chronic neutropenia are required to use Nivestim 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 Nivestim daily until their neutrophil numbers are normal. Usually, the dose is then reduced to three injections per week to maintain the neutrophil numbers. Your doctor will tell you how many injections you need each week and on which days they should be given.

Do not use the Nivestim syringe if:

The carton is open or damaged.
The needle guard is missing, detached or has been activated.
The medicine is cloudy or discoloured or the liquid has particles floating in it.
Any part of the pre-filled syringe appears cracked or broken or any of the liquid has leaked out of the syringe.
The pre-filled syringe has been dropped. The pre-filled syringe may be broken even if you cannot see the break.
The needle cover is missing or not securely attached.
The expiration date printed on the label has passed.

In all cases above, discard the prefilled syringe and use a new prefilled syringe.

Equipment required for administration

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

a new Nivestim pre-filled syringe
an alcohol swab
a puncture-resistant sharps container for disposing of used syringes safely.

Things to do before you inject

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

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

Find a clean, flat working surface, such as a table, where you can inject undisturbed.
Remove the carton containing the Nivestim pre-filled syringes from the refrigerator.
Remove the blister tray containing the pre-filled syringe from the carton. When the carton contains blister trays with more than one pre-filled syringe, tear off the blister tray containing one pre-filled syringe along the perforated part, and return the rest of the blister trays containing prefilled syringes to the carton and return the carton to the refrigerator.
Open the blister tray containing the pre-filled syringe by peeling away the lid from the blister tray. Remove the pre-filled syringe from the blister tray by grasping from the syringe body.

a. Do not grasp the grey needle cover or the plunger rod.

Check the syringe to make sure that the needle guard is covering the barrel of the pre-filled syringe. Do not push the needle guard over the needle cover before the injection. This may activate or lock the needle guard. If the needle guard is covering the needle that means it has been activated.

Check that the solution is clear, colourless and practically free from visible particles. Do not inspect the product through the plastic of the safety device.
Check the date on the syringe label to make sure that the medicine has not passed the expiry date.
For a more comfortable injection allow the pre-filled syringe to reach room temperature (approximately 25°C). This will take 15-30 minutes.

a. Do not warm Nivestim in any other way (e.g. do not warm it in the microwave or in hot water).
b. Do not shake the syringe.
c. Do not remove the needle cover until you are ready to inject.

Make sure you have your puncture-resistant sharps container nearby.
Wash and dry your hands thoroughly.

How to prepare your injection – Nivestim Ready to Use Syringe

Hold the pre-filled syringe by the body of the needle guard with the needle cover pointing up – this helps reduce the amount of medicine that may leak out of the needle.

a. Do not hold by the plunger head, or plunger or needle cover.
b. Do not pull back on the plunger at any time.
c. Do not remove the needle cover from the pre-filled syringe until you are ready to inject your medicine.

Carefully remove the needle cover by holding the barrel and pulling the cover straight off and away from your body carefully without twisting it. Throw away the cover. Do not recap the needle. Do not push the plunger or touch the exposed needle or shake the syringe.

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.
Double-check that you have the correct dose.

How to inject

Clean the site where the injection is to be made with an alcohol swab, moving the alcohol swab in an expanding circle and allow the site to dry.

Pinch a large area of skin between your thumb and forefinger, to create a firm injection site.

With your other hand, pick up the pre-filled syringe and hold it as you would a pencil.
Use a quick "dart-like" motion to insert the needle directly into the skin (at an angle of 45° or as advised by your doctor, nurse or pharmacist).

After the needle is in, pull back the plunger very slightly. If blood comes into the syringe, the needle has entered a blood vessel. Remove the needle.
Select another site, clean the new site with an alcohol swab and reinsert the needle. Again, pull back the plunger very slightly to check for blood. If blood does not appear in the syringe you are ready to inject.
Gently push down the plunger until all the contents of the prefilled syringe have been emptied.
Withdraw the needle and using the alcohol swab apply pressure for several minutes to the injection site.
Do not put the needle cover back on the used syringe. You cannot reuse the syringe.
Ensure needle guard covers the needle according to instructions for Active Needle Guard or Passive Needle Guard below.
Discard the used syringe into an approved, puncture-resistant, sharps container.

Use of Active Ultrasafe Needle Guard for Nivestim 120 µg/0.2mL solution for injection

The pre-filled syringe has an UltraSafe Active Needle Guard attached in order to protect from needle stick injury. When handling the pre-filled syringe, keep hands behind the needle.

Perform the injection using the technique described above.
When you have completed the injection, slide the needle guard forward until the needle is completely covered (device ‘clicks’ into place).

Use of Ultrasafe Passive Needle Guard for Nivestim 300 µg/0.5mL solution for injection and Nivestim 480 µg/0.5mL solution for injection

The pre-filled syringe has an UltraSafe Passive Needle Guard attached in order to protect from needle stick injury. When handling the pre-filled syringe, keep hands behind the needle.

Perform the injection using the technique described above.
Depress the plunger while grasping the finger flange until the entire dose has been given. The passive needle guard will NOT activate unless the ENTIRE dose has been given.

Remove needle from your skin, then let go of the plunger and allow syringe to move up until the entire needle is guarded and locks into place.

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

If you forget to use your injection

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

If you use too much (overdose)

If you inject more than the dose recommended by your doctor you should contact your doctor, nurse or pharmacist immediately.

Too much Nivestim may lead to neutrophil levels that are too high. Research has shown that doses almost 15 times greater than the most common dose do not immediately result in any harmful effects.

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

While you are using Nivestim

Things you must do

Be alert for any signs or symptoms of infection. There are many ways an infection may show itself.

You should watch for:

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.

If you develop any of these symptoms, go straight to your hospital.

If you are about to be started on any new medicine, tell your doctor, nurse and pharmacist that you are using Nivestim. Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you become pregnant during treatment with Nivestim, tell your doctor immediately.

Keep all of your doctor’s appointments so that your health can be monitored. Treatment with Nivestim leads to changes in the numbers of certain blood cells. Your doctor may order blood tests to check the levels of infection-fighting neutrophils and other blood cells. Blood tests may also be undertaken after you have completed your Nivestim treatment until your blood cells have returned to normal levels.

Things you must not do

Do not use Nivestim to treat any other complaint unless your doctor tells you to.

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

Side effects

Tell your doctor as soon as possible if you have any problems while using Nivestim, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, Nivestim may have unwanted side effects. Some side effects may be serious and need medical attention. Other side effects are minor and are likely to be temporary. You may also experience side effects caused by other medicines you are taking at the same time as Nivestim.

Do not be alarmed by this list of possible side effects. You may not experience any of these side effects.

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

If any of the following happen, stop taking Nivestim and go straight to hospital, as you may need urgent medical attention:

pinkish, itchy swellings on the skin, also called hives or nettle rash
swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
shortness of breath
light-headedness, dizziness or fainting
wheezing
rapid pulse, sweating.

If you experience any of these symptoms, you may have a serious allergic reaction to NEUPOGEN.

Severe allergic reactions to Nivestim are very rare.

Tell your doctor immediately if you notice any of the following:

pain in the upper left side of the abdomen
left shoulder pain
dizziness
coughing up blood or mucus
fever, chest or abdominal pain, malaise and back pain. These could be symptoms of inflammation of your aorta (the large vessel that transports blood from your heart to your body). Tell your doctor if you experience these symptoms.

The above list includes serious side effects that may require medical attention.

Tell your doctor if you notice any of the following and they worry you.

Some of these are known side effects of chemotherapy and may not be related to Nivestim:

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 medication.
abdominal discomfort
bleeding or bruising more than usual, severe nose bleeds, reddish or purplish blotches under the skin
blood in the urine
cough, breathlessness
diarrhoea
hair loss
headache
joint pain or worsening of existing arthritis
muscle pain
redness, swelling or itching at the site of injection
skin disorders – worsening of existing symptoms
skin rash or red, itchy spots
sore mouth, mouth ulcers
tiredness, looking pale

Tell your doctor, nurse or pharmacist if you notice anything that worries you or that is making you feel unwell, even if it is not on this list.

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

After using Nivestim

Storage

Keep Nivestim in a refrigerator at a temperature of 2°C to 8°C. Brief exposure to freezing temperatures (up to 24 hours) will not harm Nivestim, nor will exposure to room temperature for up to fifteen (15) days in a single period.

Do not use Nivestim if it has been left out of the refrigerator for more than fifteen (15) days, or if it has been in the freezer for more than 24 hours, or if it has been frozen more than once.

Keep Nivestim in its carton protected from light.

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

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

Disposal

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

Put the used syringe into an approved, puncture-resistant, sharps container. Dispose of the full puncture-resistant sharps container as instructed by your doctor, nurse or pharmacist.

Never put used syringes into your normal household rubbish bin.

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Nivestim is a clear, colourless solution and is supplied as ready-to-use syringes.

The single use, preservative-free syringes are packed in cartons of 1, 5, or 10 and are available in the following strengths:

120 micrograms of filgrastim in a volume of 0.2 mL;
300 micrograms of filgrastim in a volume of 0.5 mL;
480 micrograms of filgrastim in a volume of 0.5 mL.

Ingredients

The active ingredient in Nivestim is filgrastim. Other ingredients are:

water for injections
sodium
acetate
sorbitol
polysorbate 80.

Nivestim does not contain lactose, gluten, tartrazine or any other azo dyes.

Each pre-filled syringe is affixed with a needle closed by a needle cover that contains epoxyprene, a derivative of natural rubber latex which may come into contact with the needle.

Supplier

Nivestim is supplied by:

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

Australian registration numbers

120 µg/0.2mL AUST R 160106

300 µg/0.5mL AUST R 160108

480 µg/0.5mL AUST R 160107

Date of preparation

This leaflet was prepared in May 2023.

® = Registered Trademark

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Nivestim

Active ingredient

Filgrastim

Schedule

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

Each 0.2 mL pre-filled syringe contains 120 micrograms filgrastim.
Each 0.5 mL pre-filled syringe contains 300 micrograms or 480 micrograms filgrastim.
Nivestim is a 175 amino acid protein manufactured by recombinant DNA technology. Nivestim 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. Nivestim 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.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nivestim is a sterile, clear, colourless, preservative free liquid for parenteral administration, formulated in a 10 mM sodium acetate buffer at pH 4.0. The product is available in single use prefilled syringes. The single use prefilled syringes contain either 120 microgram filgrastim at a fill volume of 0.2 mL or 300 microgram or 480 microgram filgrastim at a fill volume of 0.5 mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Nivestim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs in doses not usually requiring bone marrow transplantation.
Nivestim is indicated for reducing the duration of neutropenia and clinical sequelae in patients undergoing induction and consolidation chemotherapy for acute myeloid leukaemia (AML).
Nivestim is indicated for the mobilisation of autologous peripheral blood progenitor cells (PBPCs) 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 non-myeloid malignancies.
Nivestim is indicated for the mobilisation of PBPCs, in normal volunteers, for use in allogeneic peripheral blood progenitor cell (PBPC) transplantation.
In patients receiving myeloablative chemotherapy, Nivestim is indicated for reducing the duration of neutropenia and clinical sequelae following autologous or allogeneic bone marrow transplantation.
Nivestim 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).
Nivestim 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

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 Nivestim is 5 microgram/kg/day administered as a single daily SC injection or short intravenous (IV) infusion (over 15 to 30 minutes). In phase 3 trials efficacy was observed at doses of 4 to 8 microgram/kg/day.
Nivestim 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 Nivestim 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, Nivestim 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, Nivestim 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 Nivestim is 10 microgram/kg/day given by continuous SC infusion or by IV infusion over 4 to 24 hours. Nivestim should be diluted in 25 to 50 mL of 5% glucose solution. The first dose of Nivestim 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 Nivestim 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 Nivestim 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 Nivestim 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 Nivestim for PBPC mobilisation when used alone is 10 microgram/kg/day given as a single daily SC injection or a continuous 24 hour infusion.
Nivestim 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 Nivestim 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 Nivestim 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 Nivestim 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 filgrastim for the mobilisation of PBPCs, filgrastim was administered following infusion of the collected cells. In the randomised phase 3 study, patients received filgrastim 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 Nivestim 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, Nivestim should be administered at 10 microgram/kg/day subcutaneously 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.

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

Congenital neutropenia.

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

Idiopathic or cyclic neutropenia.

The recommended daily starting dose is 5 microgram/kg subcutaneously every day (single or divided doses).
Nivestim may be administered subcutaneously 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 filgrastim were treated at doses ≤ 24 microgram/kg/day. In the SCN post-marketing surveillance study, the reported median daily doses of filgrastim 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 filgrastim ≥ 100 microgram/kg/day.

Patients with HIV infection.

For reversal of neutropenia.

The recommended starting dose of Nivestim 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 Nivestim 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. Nivestim dosing should be reduced and then stopped if myelosuppressive medication is discontinued and there is no recurrence of neutropenia.

Dilution.

If required, Nivestim may be diluted in 5% glucose solution. Nivestim 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 solution or 5% glucose plus albumin (human) solution, Nivestim 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 filgrastim is not recommended at any time. Do not dilute with saline at any time; product may precipitate. Infusion should be completed within 24 hours of the sterile dilution and transfer.
Diluted Nivestim should not be prepared more than 24 hours before administration and should be stored in the refrigerator at 2° to 8°C. To reduce microbiological hazard, the solution should be administered as soon as practicable after dilution.
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

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

4.4 Special Warnings and Precautions for Use

General warnings and precautions across all indications.

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 (e.g. clinical examination, ultrasound) due to the uncommon (≥ 1/1,000 and < 1/100) but serious risk of splenic rupture. Dose reductions of filgrastim have been noted to slow or stop the progression of splenic enlargement in patients with severe chronic neutropenia.

Patients with sickle cell disease.

Clinicians should exercise caution and monitor patients accordingly when administering Nivestim 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 Nivestim in patients with sickle cell trait or 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. Platelet counts should be monitored closely, especially during the first few weeks of filgrastim therapy. Consideration should be given to temporary discontinuation or dose reduction of filgrastim in patients with severe chronic neutropenia who develop thrombocytopenia (platelet count < 100 x 10⁹/L).

Pulmonary adverse effects.

Pulmonary adverse effects, in particular, interstitial lung disease, have been reported after G-CSF administration. There have been occasional reports of the occurrence of acute respiratory distress syndrome (ARDS) in patients receiving filgrastim. 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. Nivestim should be immediately discontinued and appropriate treatment given.
Patients with a recent history of lung infiltrates or pneumonia may be at higher risk.

Pulmonary haemorrhage and haemoptysis.

Pulmonary haemorrhage and haemoptysis requiring hospitalisation have been reported in filgrastim-treated healthy donors undergoing PBPC collection mobilisation. Haemoptysis resolved with discontinuation of filgrastim.

Glomerulonephritis.

Glomerulonephritis has been reported in patients receiving filgrastim. Generally, events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.

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

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.

Myelodysplastic syndrome or leukaemia.

The safety and efficacy of filgrastim administration in patients with MDS or chronic myeloid leukaemia 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 after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced include fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases, aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF.

Traceability.

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

Hypersensitivity.

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment, have been reported in patients treated with filgrastim. Permanently discontinue filgrastim in patients with clinically significant hypersensitivity. Do not administer filgrastim to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.

Capillary leak syndrome.

Capillary leak syndrome, which can be life-threatening if treatment is delayed, 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)).

Osteoporosis.

Monitoring of bone density according to local clinical practice may be indicated in patients with underlying osteoporotic bone diseases who undergo continuous therapy with filgrastim.

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).

Premature discontinuation of Nivestim 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, Nivestim therapy should be continued until the post nadir 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 non-haematological 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, Cancer patients receiving myelosuppressive chemotherapy, Leukocytosis).

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 tumour 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 tumour 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.
Nivestim administration should be discontinued or its dosage should be reduced if the leukocyte counts rise to > 100 x 10⁹/L.
Donors who receive Nivestim 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 (≥ 1/1,000 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.

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.

Myelodysplastic syndrome and acute myeloid leukaemia.

Cytogenetic abnormalities, transformation to MDS and AML have been observed in patients treated with filgrastim for SCN. MDS and AML have been reported to occur in the natural history of SCN without cytokine therapy. Based on available data, including a post-marketing 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, Patients with severe chronic neutropenia; 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.

ANC 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.

All patients.

Nivestim contains sorbitol (E420). Patients with rare hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary.
Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose intolerance (HFI). Medicines containing sorbitol/fructose given intravenously may be life threatening and should be contraindicated in this population, unless there is an overwhelming clinical need and no alternatives are available.
A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this medicinal product.
Nivestim contains less than 1 mmol sodium (23 mg) per 0.6 mg/mL or 0.96 mg/mL dose, that is to say essentially sodium-free.

Use in the elderly.

No special studies have been performed in the elderly and therefore no specific dosage recommendations can be made for Nivestim.

Paediatric use.

Long-term follow-up data are available from a post-marketing 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 4.4 Special Warnings and Precautions for Use, Patients with severe chronic neutropenia; 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.

Cancer patients receiving myelosuppressive chemotherapy.

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, Cancer patients receiving myelosuppressive chemotherapy, Concurrent use with chemotherapy and radiotherapy).

Lithium.

Since lithium promotes the release of neutrophils, lithium is likely to potentiate the effect of filgrastim. Although this interaction has not been formally investigated, there is no evidence that such an interaction is 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 sponsored 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 fetus.
Reproductive studies in pregnant rats have shown that filgrastim was not associated with lethal, teratogenic or behavioural effects on fetuses when administered by daily IV injection during the period of organogenesis at dose levels up to 575 microgram/kg/day. 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 fetuses 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 fetus.
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

Filgrastim may have a minor influence on the ability to drive and use machines. Dizziness may occur following the administration of filgrastim (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most serious adverse reactions that may occur during filgrastim treatment include: anaphylactic reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary leak syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or leukaemia in SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral blood cell progenitor cell transplant and sickle cell crisis in patients with sickle cell disease (see Section 4.4 Special Warnings and Precautions for Use).
The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck pain), anaemia, vomiting and nausea.

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.
Extremely rare cases of capillary leak syndrome have been reported.
Rare cases (≥ 1/10,000 to < 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, Cancer patients receiving myelosuppressive chemotherapy, 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 (≥ 1/1,000 and < 1/100) cases of splenic rupture reported in normal donors receiving G-CSFs (see Section 4.4 Special Warnings and Precautions for Use).
Extremely rare cases of capillary leak syndrome have been reported.
In normal donors, pulmonary adverse events (haemoptysis, lung infiltration) have been reported.

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, Paediatric use). Based on analysis of data from a post-marketing 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 post-marketing experience, common (≥ 1/100 and < 1/10) 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.

In combined clinical trial data, adverse reactions 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 (≥ 1/1,000 and < 1/100).

Hypersensitivity, lung infiltration and rash maculopapular.

Rare (≥ 1/10,000 and < 1/1,000).

Glomerulonephritis, extramedullary haematopoiesis, exacerbation of rheumatoid arthritis.

Comparability of Nivestim with Neupogen.

During clinical studies 183 cancer patients and 96 healthy volunteers were exposed to Nivestim. The safety profile of Nivestim observed in these clinical studies was consistent with that observed for Neupogen.

Post-marketing experience relevant to all indications.

Cases of splenomegaly have been reported commonly (≥ 1/100 and < 1/10) in patients treated with filgrastim (see Section 4.4 Special Warnings and Precautions for Use).
Cases of splenic rupture, sickle cell anaemia with crisis and glomerulonephritis have been reported uncommonly (≥ 1/1,000 and < 1/100) in patients treated with filgrastim (see Section 4.4 Special Warnings and Precautions for Use).
Cases of pulmonary haemorrhage, lung infiltration and haemoptysis have been reported in patients receiving filgrastim (see Section 4.4 Special Warnings and Precautions for Use). Interstitial lung disease, pulmonary oedema and hypoxia have also been reported.
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.

Description of selected adverse reactions.

Hypersensitivity.

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension occurring on initial or subsequent treatment have been reported in clinical studies and in post-marketing experience. Overall, reports were more common after IV administration.
In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Filgrastim should be permanently discontinued in patients who experience a serious allergic reaction.

Capillary leak syndrome.

Cases of capillary leak syndrome have been reported 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).

Cutaneous vasculitis.

Cutaneous vasculitis has been reported in patients treated with filgrastim. The mechanism of vasculitis in patients receiving filgrastim is unknown. During long-term use, cutaneous vasculitis has been reported in SCN patients.

Leukocytosis.

Leukocytosis (WBC > 50 x 10⁹/L) was observed in 41% of normal donors and transient thrombocytopenia (platelets < 100 x 10⁹/L) following filgrastim and leukapheresis was observed in 35% of donors (see Section 4.4 Special Warnings and Precautions for Use).

Sweets syndrome.

Cases of Sweets syndrome (acute febrile neutrophilic dermatosis) have been reported in patients treated with filgrastim.

GvHD.

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

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 Nivestim 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 Nivestim 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 Nivestim 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 pre-treatment levels in 1 to 7 days.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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).
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 Nivestim with Neupogen.

Nivestim and Neupogen have been demonstrated to be pharmacodynamically equivalent in vivo and in healthy volunteers.
An in vivo study compared the efficacy of Nivestim and Neupogen using a cyclophosphamide (CPA) induced neutropenic model in male rats. Nivestim and Neupogen induced a comparable neutrophilic pharmacodynamic response following daily SC injections of 30 microgram/kg/dose or 100 microgram/kg/dose for 4 days. In a 28-day repeat dose toxicity study, Nivestim and Neupogen demonstrated comparable statistically significant dose dependent increases in the number of circulating neutrophils.
Pharmacodynamic properties of Nivestim and Neupogen were compared in a single-dose phase I study in healthy volunteers. IV and SC administration of single 10 microgram/kg doses provided similar ANC values (see Table 3).

Pharmacodynamic properties of Nivestim and Neupogen were also compared in a multiple dose phase I study in healthy volunteers. SC administration of multiple (five) 5 microgram/kg and 10 microgram/kg doses provided similar ANC AUC_(0-tlast) and CD34⁺ values (see Tables 4 and 5).

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 collection and therapy.

Use of filgrastim, either alone, or after chemotherapy, mobilises haemopoietic progenitor cells into the peripheral blood. These 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 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.

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, non-comparative 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, co-trimoxazole 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 and 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 Nivestim with Neupogen.

Therapeutic equivalence of Nivestim and Neupogen was demonstrated in a double blind, randomised, controlled phase 3 trial of patients receiving doxorubicin and docetaxel as combination therapy for invasive breast cancer. 279 patients were randomised (2:1) to 5 microgram/kg Nivestim (n = 184) or 5 microgram/kg Neupogen (n = 95). Up to six cycles of treatment were administered at 3-weekly intervals.
The mean duration of severe neutropenia (DSN) (ANC < 0.5 x10⁹/L) in cycle 1 was 1.6 days in the Nivestim group compared with 1.3 days in the Neupogen group. The 90% CI for the difference of the treatment means lies within the predefined range -1 to +1 day. Analysis of DSN in cycle 1 gave adjusted means (adjusted for treatment setting) of 1.85 days (95% CI 1.63-2.08) for Nivestim and 1.47 days (95% CI 1.19-1.75) for Neupogen, with a difference between the two treatment groups means of 0.38 (95% CI, 0.08-0.68).
In subjects with severe neutropenia, the majority (93.3%) of subjects in the Nivestim group and all (100%) subjects in the Neupogen group had a DSN of less than 3 days. Eleven subjects (6.7%) in the Nivestim group had a DSN of 4 or 5 days: 10 (6.1%) had a DSN of 4 days and 1 (0.8%) had a DSN of 5 days. Of the 10 subjects in the Nivestim group with a DSN of 4 days, two had febrile neutropenia (ANC < 0.5 x 10⁹/L and body temperature ≥ 38.5°C) in the same cycle. The one subject with a DSN of 5 days also had febrile neutropenia in the same cycle.
Time to ANC Recovery (ANC > 3 x 10⁹/L) was similar in both treatment groups. Mean time to ANC recovery in cycle 1 was 7.8 days in both the Nivestim and Neupogen groups; in cycles 2 and 3, mean time to ANC recovery was 7.4 days and 7.5 days for the Nivestim group and 7.6 days in both cycles for the Neupogen group.

5.2 Pharmacokinetic Properties

In normal volunteers, serum filgrastim concentrations declined monoexponentially following a single 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.
SC 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 Nivestim with Neupogen.

Equivalent pharmacokinetic (PK) profiles of Nivestim and Neupogen have been demonstrated in healthy volunteers in a single-dose phase I study and a multiple-dose phase I study.
Mean values for AUC_(0-tlast) and C_max were similar between treatment groups following IV and SC administration of single 10 microgram/kg doses of Nivestim and Neupogen. See Tables 6 and 7.

PK parameters in the multiple-dose study were assessed as secondary endpoints. Mean values for AUC_(0-tlast) and C_max following multiple (five) SC 5 microgram/kg and 10 microgram/kg doses of Nivestim and Neupogen were as follows. See Tables 8 and 9.

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 micronuclear 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glacial acetic acid, polysorbate 80, sodium hydroxide, sorbitol, water for injections.

6.2 Incompatibilities

Nivestim should not be diluted with sodium chloride solutions.
Diluted filgrastim may be adsorbed to glass and plastic materials unless it is diluted in 5% glucose solution (see Section 4.2 Dose and Method of Administration, Dilution).
This medicinal product must not be mixed with other medicinal products except those mentioned, see Section 4.2 Dose and Method of Administration.

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.
Diluted Nivestim should not be prepared more than 24 hours before administration and should be stored in the refrigerator at 2° to 8°C. To reduce microbiological hazard, the solution should be administered as soon as practicable after dilution.

6.4 Special Precautions for Storage

Nivestim should be stored in the refrigerator at 2 to 8°C. Keep Nivestim in its outer carton in order to protect from light. Prior to injection, Nivestim may be allowed to reach room temperature. Avoid vigorous shaking.
Within its shelf-life and for the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 15 days. At the end of this period, the product should not be put back in the refrigerator and should be disposed of. Accidental exposure to freezing temperatures for up to 24 hours does not affect the stability of Nivestim. The frozen pre-filled syringes can be thawed and then refrigerated for future use. If exposure has been greater than 24 hours or frozen more than once, then Nivestim should not be used.

6.5 Nature and Contents of Container

Nivestim 120 microgram/0.2 mL syringe for SC or IV injection.

Single use, preservative-free syringes containing 120 microgram (0.2 mL) of filgrastim (600 microgram/mL). Single pack, box of 5 and box of 10.

Nivestim 300 microgram/0.5 mL syringe for SC or IV injection.

Single use, preservative-free syringes containing 300 microgram (0.5 mL) of filgrastim (600 microgram/mL). Single pack, box of 5 and box of 10.

Nivestim 480 microgram/0.5 mL syringe for SC or IV injection.

Single use, preservative-free syringes containing 480 microgram (0.5 mL) of filgrastim (960 microgram/mL). Single pack, box of 5 and box of 10.
Each pre-filled syringe is affixed with a needle closed by a needle cover that contains epoxyprene, a derivative of natural rubber latex which may come into contact with the needle.

6.6 Special Precautions for Disposal

Product is for single use in one patient only. Discard any residue.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

A schematic diagram of the amino acid sequence is provided below:

CAS number.

121181-53-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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