Consumer medicine information

Ziextenzo

Pegfilgrastim

BRAND INFORMATION

Brand name

Ziextenzo

Active ingredient

Pegfilgrastim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ziextenzo.

SUMMARY CMI

Ziextenzo®

Consumer Medicine Information (CMI) summary

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

1. Why am I using Ziextenzo?

Ziextenzo contains the active ingredient pegfilgrastim. Ziextenzo is used to help fight infection, following chemotherapy.

For more information, see Section 1. Why am I using Ziextenzo? in the full CMI.

2. What should I know before I use Ziextenzo?

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

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

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

3. What if I am taking other medicines?

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

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Ziextenzo?

  • Ziextenzo is given by injection, into the tissues just below the skin. This is called a subcutaneous injection.
  • 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 give yourself the injection at home.

More instructions can be found in Section 4. How do I use Ziextenzo? in the full CMI.

5. What should I know while using Ziextenzo?

Things you should do
  • Watch for any signs or symptoms of infection.
  • Remind any doctor, dentist or pharmacist you visit that you are using Ziextenzo.
  • Be sure to keep all your doctor's appointments so your progress can be checked.
Things you should not do
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how Ziextenzo affects you.

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

6. Are there any side effects?

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

Some of the more common and serious side effects are included in full below in the CMI. Speak to your doctor if you have any of these side effects and they worry you.

A very serious side effect is allergic reactions, the symptoms are:

  • rash over a large area of the body, itching or hives
  • shortness of breath, wheezing or difficulty breathing
  • coughing up blood, bleeding from the lung
  • swelling of the face, lips, tongue or other parts of the body
  • faintness
  • rapid pulse or sweating

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Ziextenzo®

Active ingredient(s): pegfilgrastim

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Ziextenzo?

Ziextenzo contains the active ingredient pegfilgrastim. Ziextenzo is a long acting form of Recombinant Human Granulocyte Colony Stimulating Factor or GCSF. Using gene technology, Ziextenzo 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 the infections.

G-CSF also helps neutrophils to do this work better.

Ziextenzo is used to help fight infection, following chemotherapy.

Some chemotherapy will reduce the number of neutrophils in your body. Although Ziextenzo is not a treatment for cancer, it does help the body to make new neutrophils. 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.

2. What should I know before I use Ziextenzo?

Warnings

Do not use Ziextenzo if:

  • you are allergic to pegfilgrastim, filgrastim or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are allergic to any medicines or products that are produced using the bacteria, E. coli.

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
  • skin rash, itching or hives.

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

Do not use Ziextenzo within 24 hours after you receive chemotherapy. This is because the chemotherapy medicine may stop Ziextenzo from increasing the number of infection-fighting neutrophils.

Do not use Ziextenzo if it has been left out of the refrigerator for more than three days.

Check with your doctor if you:

  • have or have had any other medical conditions, including:
    - a medical condition affecting the bone marrow or blood
    - a family history of a genetic disorder
    - sickle cell disease
    - problems with your kidneys, liver, heart or other organs
    - previous treatment for cancer
    - any infections, cancers or tumours
    - allergies to any other medicines, foods, preservatives or dyes
  • take any medicines for any other condition.

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

Pregnancy and breastfeeding

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

Tell your doctor immediately if you become pregnant while taking this medicine.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

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

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

4. How do I use Ziextenzo?

Ziextenzo is given by injection, into the tissues just below the skin. This is called a subcutaneous injection.

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 Ziextenzo injection at home.

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

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

How much to take

  • The usual dose is one subcutaneous injection 24 hours after the end of each chemotherapy cycle.
  • Follow the instructions provided and use Ziextenzo until your doctor tells you to stop.

When to take Ziextenzo

  • Ziextenzo should be used 24 hours after the end of each chemotherapy cycle.

How to take Ziextenzo

  • To help avoid possible infections and to ensure that you use the medicine correctly, it is important that you follow these instructions.
  • Read ALL the way through these instructions before injecting. It is important not to try to inject yourself until you have been trained by your doctor, nurse or pharmacist. The carton contains the pre-filled syringe individually sealed in a plastic blister.

Your Ziextenzo pre-filled syringe with needle guard

After the medicine has been injected, the needle guard will be activated to cover the needle. The needle guard is intended to protect healthcare professionals, caregivers and patients from accidental needle stick injuries after the injection.

What you additionally need for your injection:

  • Alcohol swab.
  • Cotton ball or gauze.
  • Sharps disposal container.

Important safety information

Caution: Keep the pre-filled syringe out of the sight and reach of children.

  1. Do not open the carton until you are ready to use the pre-filled syringe.
  2. Do not use the pre-filled syringe if the seal of the blister is broken, as it may not be safe for you to use.
  3. Do not use the pre-filled syringe if there is liquid in the blister. Do not use the pre-filled syringe if the needle cap is missing or not securely attached. In all these instances, return the entire product pack to the pharmacy.
  4. Never leave the pre-filled syringe unattended where others might tamper with it.
  5. Do not shake the pre-filled syringe.
  6. Be careful not to touch the needle guard wings before use. By touching them, the needle guard may be activated too early.
  7. Do not remove the needle cap until just before you give the injection.
  8. The pre-filled syringe cannot be re-used. Dispose of the used syringe immediately after use in a sharps container.
  9. Do not use if the syringe has been dropped onto a hard surface or dropped after removing the needle cap.

Storage of the Ziextenzo pre-filled syringe

  1. Store the blistered pre-filled syringe in its carton to protect it from light.
  2. Store in the refrigerator between 2 °C and 8 °C. Do not freeze.
  3. Prior to use, remove the pre-filled syringe from the refrigerator and allow Ziextenzo to reach room temperature (up to a maximum of 35 °C) for approximately 15-30 minutes.
  4. Do not use the pre-filled syringe after the expiry date which is stated on the carton or syringe label. If it has expired, return the entire pack to the pharmacy.

The injection site

The injection site is the place on the body where you are going to use the pre-filled syringe.

  • The recommended site is the front of your thighs. You may also use the lower abdomen, but not the area 5 centimetres around the navel (belly button).
  • Choose a different site each time you give yourself an injection.
  • Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks.

If a caregiver is giving you the injection, the outer upper arms may also be used.

Preparing the Ziextenzo pre-filled syringe ready for use

  1. Take the carton containing the blistered pre-filled syringe out of the refrigerator and leave it unopened for approximately 15-30 minutes so that it reaches room temperature.
  2. When you are ready to use the pre-filled syringe, open the blister and wash your hands thoroughly with soap and water.
  3. Clean the injection site with an alcohol swab.
  4. Remove the pre-filled syringe from the blister by holding it in the middle as shown below. Do not grab the plunger. Do not grab the needle cap.

  1. Check to ensure the plastic transparent needle guard is situated over the barrel of the glass syringe. If the transparent needle guard is covering the needle cap (as shown below) the syringe needle guard has been activated, DO NOT use this syringe and take a new syringe. The figure below shows a ready to use syringe.

Device ACTIVATED – DO NOT USE

In this configuration the needle guard is ACTIVATED – DO NOT USE the pre-filled syringe

Device READY TO BE USED

In this configuration the needle guard is NOT ACTIVATED and the pre-filled syringe is ready for use

  1. Inspect the pre-filled syringe. The liquid should be clear. Its colour may vary from colourless to slightly yellowish. You may see a small air bubble in the liquid. This is normal. Do not use the pre-filled syringe if any other particulates and/or discolouration are observed.
  2. Do not use if the syringe is broken or activated. Return the Ziextenzo pre-filled syringe and the package to your pharmacy.

How to use the Ziextenzo pre-filled syringe

  1. Carefully pull the needle cap straight off. Discard the needle cap. You may see a drop of liquid at the end of the needle. This is normal.

  1. Gently pinch the skin at the injection site and insert the needle as shown. Push the needle all the way in to ensure that the medicine can be fully administered.

  1. Holding the pre-filled syringe as shown, slowly depress the plunger as far as it will go so that the plunger head is completely between the needle guard wings.
Keep the plunger pressed fully down while you hold the syringe in place for 5 seconds.

  1. Keep the plunger fully depressed while you carefully pull the needle straight out from the injection site and let it go off your skin.

  1. Slowly release the plunger and allow the syringe needle guard to automatically cover the exposed needle.
There may be a small amount of blood at the injection site. You can press a cotton ball or gauze onto the injection site and hold it for 10 seconds. Do not rub the injection site. You may cover the injection site with a small adhesive bandage, if needed.

  1. Healthcare providers only
The trade name of the administered product should be clearly recorded in the patient file. Remove and save the pre-filled syringe label.
Turn the plunger to move the label into a position where you can remove the syringe label.

  1. Disposal instructions
Dispose of the used syringe in a sharps container (closable, puncture resistant container).
Do not throw away any medicines via wastewater or household waste. Ask your doctor or pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. Any unused product or waste material should be disposed of in accordance with local requirements.

If you forget to use Ziextenzo

If you miss your scheduled dose, talk to your doctor, nurse or pharmacist as soon as possible.

If you use too much Ziextenzo

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

You should immediately:

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

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

5. What should I know while using Ziextenzo?

Things you should do

Watch for any signs or symptoms of infection.

There are many ways an infection may show itself. Symptoms of an infection include:

  • fever (a temperature of 38.2°C or greater, or as your doctor suggests)
  • chills
  • rash
  • sore throat
  • diarrhoea
  • earache
  • difficult or painful breathing, coughing or wheezing.

Go straight to your hospital if you develop any of these symptoms.

If you are about to be started on any new medicine, tell your doctor, nurse and pharmacist that you are using Ziextenzo.

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

Keep all of your doctor's appointments so that your health can be monitored. Your doctor may order blood tests to check the levels of infection-fighting neutrophils and other blood cells.

Things you should not do

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

Driving or using machines

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

Looking after your medicine

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

Keep Ziextenzo in a refrigerator at a temperature of 2°C to 8°C.

Do not freeze.

Do not use Ziextenzo if you think it has been frozen. Exposure to room temperature of up to 3 days will not harm Ziextenzo.

Keep your medicine in its pack.

Protect it from light.

Keep it where young children cannot reach it.

Disposal

Once you have injected Ziextenzo, do not put the grey needle cap back on the used syringe.

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

Never put the used syringes into your normal household rubbish bin.

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

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
  • temporary bone pain, such as in the lower back or in the long bones of the arms or legs
    This pain is usually relieved with non-prescription painkillers, like paracetamol. If you continue to have bone pain even after having taken this form of pain relief, you should speak to your doctor, as you may need a prescription medicine.
  • headache
  • general aches and pains in joints and muscles
  • reddish or purplish blotches under the skin
  • injection site pain and redness of the skin at the injection site
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • pain in the upper left side of the stomach (abdomen)
  • left shoulder pain
  • dizziness
  • fever and painful skin lesions most commonly on your arms, legs and sometimes on your face and neck
  • blood in the urine
  • tiredness, shortness of breath, easy bleeding and frequent infections.
  • swelling or puffiness
  • less frequent urination
  • swelling of your stomach-area (abdomen) and feeling of fullness
  • general feeling of tiredness.
Tell your doctor as soon as possible or go straight to the Emergency Department at your nearest hospital if you experience any of the following symptoms.

Very serious side effects

Very serious side effectsWhat to do
  • rash over a large area of the body, itching or hives
  • shortness of breath, wheezing or difficulty breathing
  • coughing up blood, bleeding from the lung
  • swelling of the face, lips, tongue or other parts of the body
  • faintness
  • rapid pulse or sweating.
Stop taking the medicine and go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What Ziextenzo contains

Active ingredient
(main ingredient)		pegfilgrastim
Other ingredients
(inactive ingredients)		acetic acid, sorbitol, polysorbate 20, Water for Injections.
Potential allergensZiextenzo does not contain lactose, gluten, tartrazine or any other azo dyes.

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

What Ziextenzo looks like

Ziextenzo is a clear, colourless solution. It is supplied in a carton as a pre-filled syringe with an automatic needle guard. (Aust R 308367).

The syringe and needle guard do not contain natural rubber latex or any derivatives.

Who distributes Ziextenzo

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was prepared in February 2024.

® Registered trademark. The trademarks mentioned in this material are the property of their respective owners.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Ziextenzo

Active ingredient

Pegfilgrastim

Schedule

S4

 

1 Name of Medicine

Ziextenzo (pegfilgrastim) is a long-acting form of recombinant human granulocyte colony-stimulating factor (G-CSF).

2 Qualitative and Quantitative Composition

Each 0.6 mL single use pre-filled syringe with an automatic needle guard contains 6 mg of pegfilgrastim.
Ziextenzo (pegfilgrastim) is composed of filgrastim (recombinant methionyl human G-CSF) with an approximately 20,000 dalton polyethylene glycol (PEG) molecule covalently bound to the N-terminal methionine residue.
Filgrastim is a 175 amino acid protein manufactured by recombinant DNA technology. Filgrastim is produced by Escherichia coli (E. coli) bacteria into which has been inserted the human G-CSF gene. Filgrastim is unglycosylated and contains an N-terminal methionine necessary for expression in E. coli. Pegfilgrastim has a total molecular weight of approximately 39,000 daltons.
Ziextenzo (pegfilgrastim) is a biosimilar medicine to Neulasta.
The comparability of Ziextenzo with Neulasta has been demonstrated with regard to physicochemical characteristics and efficacy and safety outcomes [see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects)]. The evidence for comparability supports the use of Ziextenzo for the listed indication.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ziextenzo is a sterile, clear, colourless to slightly yellowish, preservative-free liquid for subcutaneous (SC) administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Ziextenzo is indicated for the treatment of cancer patients following chemotherapy, to decrease the duration of severe neutropenia and so reduce the incidence of infection, as manifested by febrile neutropenia.

4.2 Dose and Method of Administration

Dosage (dose and interval).

The recommended dosage of Ziextenzo is a single SC injection of 6 mg administered once per chemotherapy cycle. Ziextenzo should be administered approximately 24 hours after the administration of cytotoxic chemotherapy. In clinical studies, pegfilgrastim has been safely administered 14 days before chemotherapy (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Ziextenzo contains no antimicrobial agent. Ziextenzo is for single use in 1 patient only. Discard any residue.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Do not use any products exhibiting particulate matter or discolouration.
Avoid shaking. Allow the ready to use pre-filled syringe with automatic needle guard to reach room temperature before injecting.

4.3 Contraindications

Ziextenzo is contraindicated in patients with known hypersensitivity to E. coli-derived proteins, pegfilgrastim, filgrastim, or any other component of the product.

4.4 Special Warnings and Precautions for Use

Traceability.

In order to improve the traceability of biological medicines, the trade name and the batch number of the administered product should be clearly recorded in the patient's medical record and/or dispensing record.

Splenomegaly and splenic rupture.

Cases of splenic rupture, including some fatal cases, have been reported following the administration of pegfilgrastim. Patients who report left upper abdominal pain and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture.

Sickle cell crisis.

Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell disease. Clinicians should exercise caution, monitor patients accordingly when administering Ziextenzo to patients with sickle cell trait or sickle cell disease and only consider use after careful evaluation of the potential benefits and risks.

Pulmonary haemorrhage and haemoptysis.

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

Acute respiratory distress syndrome.

In patients with sepsis receiving Ziextenzo, the physician should be alert to the possibility of acute respiratory distress syndrome, due to the possible influx of neutrophils at the site of inflammation.

Glomerulonephritis.

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

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

In the post-marketing observational study setting, myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) have been associated with the use of pegfilgrastim 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.

Concurrent use with chemotherapy and radiotherapy.

The safety and efficacy of pegfilgrastim 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 pegfilgrastim is not recommended in the period 24 hours after the administration of chemotherapy (see Section 4.2 Dose and Method of Administration). In clinical studies, pegfilgrastim has been safely administered 14 days before chemotherapy. Clinical trials with pegfilgrastim have not involved patients treated with fluorouracil or other antimetabolites. In studies in mice, administration of pegfilgrastim at 0, 1 and 3 days before fluorouracil resulted in increased mortality; administration of pegfilgrastim 24 hours after fluorouracil did not adversely affect survival.
The safety and efficacy of pegfilgrastim have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, e.g. nitrosoureas.
The safety and efficacy of pegfilgrastim have not been evaluated in patients receiving radiotherapy.

Use in myelodysplasia and leukaemia.

The safety and efficacy of pegfilgrastim administration in patients with myelodysplasia or chronic myeloid leukaemia have not been established.
Randomised studies of filgrastim in patients undergoing chemotherapy for acute myeloid leukaemia demonstrate no stimulation of disease as measured by remission rate, relapse and survival.

Leukocytosis.

In pegfilgrastim clinical studies self-limiting leukocytosis (WBC counts > 100 x 109/L) have been reported in < 0.5% of 930 subjects with non-myeloid malignancies receiving pegfilgrastim. Leukocytosis was not associated with any reported adverse clinical effects.

Immunogenicity.

As with all therapeutic proteins, there is potential for immunogenicity. Rates of antibody generation against pegfilgrastim 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.

Thrombocytopenia and anaemia.

Thrombocytopenia has been reported in patients receiving pegfilgrastim. Platelet counts should be monitored closely.
In studies of pegfilgrastim 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 for patients to receive higher doses of chemotherapy (i.e. full doses on the prescribed schedule for a longer period), patients may be at greater risk of thrombocytopenia which should be monitored carefully. Anaemia and non-haematologic consequences of increased chemotherapy doses (please refer to the prescribing information for specific chemotherapy agents used) may also occur. If there is a risk of these conditions regular monitoring of the complete blood count is recommended. Furthermore, care should be exercised in the administration of Ziextenzo in conjunction with drugs known to lower the platelet count and in the presence of moderate or severe organ impairment.

Aortitis.

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

Laboratory monitoring.

To assess a patient's haematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Pegfilgrastim produced absolute neutrophil count (ANC) profiles similar to daily filgrastim, including earlier ANC nadir, shorter duration of severe neutropenia and accelerated ANC recovery, compared with ANC profiles observed without growth factor support. Due to neutrophil mediated clearance, pegfilgrastim is likely to produce post-recovery ANC levels in the normal range, and the above-normal peak ANC levels commonly seen with daily filgrastim do not occur.

Use in hepatic impairment.

See Section 5.2 Pharmacokinetic Properties.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties.

Paediatric use.

See Section 5.2 Pharmacokinetic Properties.

Effects on laboratory tests.

None known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug interactions between pegfilgrastim and other drugs have not been fully evaluated.

Bone imaging.

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

Lithium.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Pegfilgrastim did not affect the fertility of male or female rats when administered once weekly at SC doses of up to 1 mg/kg (about 2 to 13x the recommended human dose of 6 mg based on plasma AUC data for a single dose).
(Category B3)
Pegfilgrastim crosses the placenta in pregnant rats. Administration of pegfilgrastim every second day over the period of organogenesis to rats and rabbits at SC doses up to 1 mg/kg and 200 microgram/kg, respectively, produced no evidence of teratogenicity. The rat dose was 2-fold of the anticipated exposure at the maximal recommended human dose (based on AUC), while the rabbit dose was 0.6-fold the human dose (based on body surface area). An increased incidence of wavy ribs, considered a reversible change, was observed in rats at doses greater than 100 microgram/kg.
Decreased maternal body weight gain, accompanied by decreased maternal food consumption and decreased fetal body weights were observed in rabbits at doses of 50 microgram/kg SC and above. Increased post-implantation loss due to early resorptions and an increased incidence of abortions were observed at pegfilgrastim doses above 50 microgram/kg SC. Once weekly SC injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 microgram/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon fertility indices.
There are no adequate and well-controlled studies in pregnant women. Ziextenzo should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
 Whether pegfilgrastim is excreted in human milk is not known. Because many drugs are excreted in human milk, caution should be exercised if Ziextenzo is administered to breastfeeding women.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Safety data are based on seven randomised clinical trials involving over 930 patients with lymphoma and solid tumours (breast, lung and thoracic tumours) receiving pegfilgrastim after non-myeloablative cytotoxic chemotherapy. Most adverse experiences were the sequelae of the underlying malignancy or cytotoxic chemotherapy. They occurred at similar rates in subjects who received pegfilgrastim (n = 930), filgrastim (n = 331) or placebo (n = 463). These adverse experiences occurred at rates between 15% and 72%. They included: nausea, fatigue, alopecia, diarrhoea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalised weakness, peripheral oedema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. The most common observed adverse reaction related to pegfilgrastim therapy was medullary bone pain, which was reported in 26% of patients. This was comparable to the incidence of medullary bone pain related to filgrastim therapy. This bone pain was generally reported to be of mild-to-moderate severity, could be controlled in most patients with non-narcotic analgesics, and had a comparable duration for both pegfilgrastim and filgrastim-treated patients. Infrequently, bone pain was severe enough to require narcotic analgesics. No patient withdrew from the study due to bone pain. In these randomised clinical trials, the following adverse events related to pegfilgrastim were reported. See Tables 1 and 2.
Across all studies, no life-threatening or fatal adverse events were attributed to pegfilgrastim. In these studies, there was only 1 serious adverse event (dyspnoea) reported in a single patient as possibly related to pegfilgrastim.
Spontaneously reversible elevations in lactate dehydrogenase (LDH), alkaline phosphatase and uric acid of mild-to-moderate severity were observed. Most changes have been attributed to post-cytokine bone marrow expansion as well as to chemotherapy and metastatic disease. The incidences of these changes, presented for pegfilgrastim relative to filgrastim and placebo, were: LDH (18% versus 29% and 18%), alkaline phosphatase (11% versus 16% and 12%) and uric acid (11% versus 9% and 13% [1% of reported cases for pegfilgrastim and filgrastim groups were classified as severe]).

Post marketing experience.

Extremely rare cases of capillary leak syndrome have been reported in subjects receiving filgrastim, the parent compound of pegfilgrastim.
Allergic Reactions: Allergic-type reactions, including anaphylactic reactions, skin rash, urticaria and erythema/flushing occurring on initial or subsequent treatment have been reported in patients receiving pegfilgrastim. In some cases, symptoms have recurred with rechallenge, suggesting a causal relationship. Allergic-type reactions to pegfilgrastim have rarely been reported in post-marketing experience.
If a serious reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Ziextenzo should be permanently discontinued in patients who experience a serious allergic reaction.
Injection site pain and erythema have been reported in patients receiving pegfilgrastim.
Cases of glomerulonephritis have been reported uncommonly (≥ 1/1000 and < 1/100) in patients receiving pegfilgrastim.
Cases of pulmonary haemorrhage and haemoptysis have been reported in patients receiving pegfilgrastim.
Cases of aortitis have been reported in patients receiving pegfilgrastim.
Rare cases (≥ 1/10,000 and < 1/1,000) of Sweet's syndrome (acute febrile dermatosis), splenomegaly, splenic rupture and sickle cell crisis have been reported in patients receiving pegfilgrastim.
Cases of thrombocytopenia have been reported commonly (≥ 1/100 and < 1/10) in patients receiving pegfilgrastim.
Cases of myelodysplastic syndrome and acute myeloid leukaemia have been reported in breast and lung cancer patients receiving chemotherapy and/or radiotherapy.
Very rare (< 1/10,000) reactions of cutaneous vasculitis have been reported in patients receiving pegfilgrastim.
There has been no evidence for the development of neutralising antibodies, or of a blunted or diminished response to pegfilgrastim in treated patients, including those receiving up to 6 cycles of pegfilgrastim.

Comparability of Ziextenzo with the reference medicine in terms of safety.

Similar safety profiles between Ziextenzo and the reference medicine were observed in the clinical studies in healthy volunteers, as well as in patients with breast cancer.

Common adverse events in healthy subjects.

In the Phase 1 PK/PD study in healthy volunteers, the pattern and nature of adverse events (AEs) reported after administration of Ziextenzo were consistent with the safety profile of the reference medicine. Most commonly observed adverse events were bone pain, myalgia, arthralgia and back pain.

Common adverse events in patients.

Studies LA-EP06-301 and LA-EP06-302 were double-blind, randomised, parallel-group, multi-center studies of similar design and were conducted in female patients with breast cancer receiving established myelosuppressive chemotherapy. Patients were randomised to either Ziextenzo or the reference product administered on Day 2 of each chemotherapy (docetaxel (75 mg/m2) in combination with doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2) cycle for up to 6 cycles. Treatment duration was up to 18 weeks in both studies.
In both studies, study drug administration was 6 mg dose SC in every cycle.
Studies LA-EP06-301 and LA-EP06-302 independently showed similar safety results: the overall incidences and pattern of AEs were similar in the Ziextenzo treatment groups compared with the reference product treatment groups of both studies and are consistent with reported data for the reference product. In addition, the findings are consistent with the nature of the underlying disease and the safety profiles of the chemotherapeutic agents.
AEs that were reported in these studies are shown by preferred term in Table 3.
The safety profile of Ziextenzo was similar to the safety profile of the reference medicine with no clinically meaningful differences observed in healthy volunteers or patients.

Comparability of Ziextenzo with the reference medicine in terms of immunogenicity.

Immunogenicity of Ziextenzo and the reference medicine was compared in healthy subjects and breast cancer patients. Overall there was low immunogenicity which is consistent with data reported for the reference medicine.
The incidence of ADAs (anti-drug antibodies) post treatment was similarly low in all treatment groups, the detected ADAs were non-neutralizing and clinically not relevant. There was no unusual behaviour noted in individual PK and absolute neutrophil count (ANC) profiles indicative of potential effects of ADAs on pegfilgrastim systemic clearance or on the production and release of neutrophils.
The low detection rate of ADAs post treatment in both healthy volunteers and breast cancer patients and the absence of NAbs (neutralizing antibodies) in all three studies is consistent with data reported with the reference medicine.

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

There is no experience with overdose of pegfilgrastim in humans. In subjects administered doses of up to 5 times the recommended dose, adverse events were similar to those observed in subjects administered lower doses of pegfilgrastim.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Human G-CSF is a glycoprotein which regulates the production and release of neutrophils from the bone marrow. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo compared to filgrastim. Pegfilgrastim and filgrastim have been shown to have identical modes of action. They cause a marked increase in peripheral blood neutrophil counts within 24 hours in subjects with healthy bone marrow, with minor increases in monocytes and/or lymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function.

Pharmacodynamic comparability of Ziextenzo with the reference medicine.

Pharmacodynamic (PD) similarity of Ziextenzo was demonstrated in a single-dose, two-period crossover study in healthy subjects with a single SC administration of Ziextenzo and the reference medicine.
PD similarity was shown in healthy subjects using absolute neutrophil count over time. PD similarity between Ziextenzo and the reference medicine was demonstrated with the lower and upper bounds of the 95% CIs (confidence intervals) of the geometric mean ratios of the primary PD endpoints AUEC0-last and Emax being entirely contained within the pre-defined margins of 0.80 to 1.25. See Table 4.

Clinical trials.

Three pivotal, randomised, double-blind clinical studies have been conducted in patients with solid tumours receiving a variety of chemotherapy regimens. Pegfilgrastim administered 24 hours after chemotherapy in the first cycle and all subsequent cycles of chemotherapy has been shown to be safe and effective in reducing neutropenia and associated clinical sequelae.
Studies 1 and 2 met the primary objective of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients ([ANC] < 0.5 x 109/L) did not exceed that of filgrastim-treated patients by more than one day in cycle 1 of chemotherapy.
Results from Study 1, a randomised, double-blind study conducted in patients with breast cancer (n = 155) undergoing 4 cycles of the highly myelosuppressive chemotherapy regimen doxorubicin and docetaxel (AT), demonstrated a clinically and statistically similar reduction in the duration of severe neutropenia (ANC < 0.5 x 109/L) in cycle 1 in patients who received pegfilgrastim as a fixed dose of 6 mg compared with patients who received a mean of 11 daily injections of filgrastim 5 microgram/kg/day (see Table 5). Durations of severe neutropenia were also comparable between treatment groups in all subsequent cycles. There was no significant difference in the incidence of febrile neutropenia between the groups in Study 1.
In study 2, patients with breast cancer (n = 301) were randomised to receive a single injection of pegfilgrastim 100 microgram/kg or daily injections of filgrastim 5 microgram/kg/day after each of 4 cycles of the highly myelosuppressive chemotherapy regimen doxorubicin and docetaxel (AT). In cycle 1, a single SC injection of pegfilgrastim resulted in a duration of severe neutropenia that was clinically and statistically similar to that observed after a mean of 11 daily injections of filgrastim (see Table 5). Durations of severe neutropenia were also comparable between treatment groups in all subsequent cycles. There is a significant difference in the incidence of febrile neutropenia between the groups in Study 2.
Study 3 was a placebo-controlled study evaluating the effect of pegfilgrastim on the incidence of febrile neutropenia following administration of a moderately myelosuppressive chemotherapy regimen (docetaxel 100 mg/m2 q 3 weeks for 4 cycles). This regimen is associated with a febrile neutropenia rate of up to 20%. In this study, 928 patients were randomised to receive either pegfilgrastim or placebo on Day 2 of each cycle. The incidence of patients with febrile neutropenia, was significantly lower in the patients randomised to receive pegfilgrastim vs placebo (1% vs 17%, p < 0.001, respectively). The incidence of hospitalisation and IV anti-infective use associated with a clinical diagnosis of febrile neutropenia was significantly lower in patients randomised to pegfilgrastim compared to placebo (1% vs 14%, p < 0.001; and 2% vs 10%, p < 0.001, respectively).
Data from phase 2 studies in patients with various malignancies undergoing a variety of chemotherapy regimens further support the safety and efficacy of pegfilgrastim. Dose-finding studies in patients with breast cancer (n = 152), thoracic tumours (n = 92) and non-Hodgkin's lymphoma (NHL) (n = 50) demonstrated that the efficacy of a single injection of pegfilgrastim 100 microgram/kg was similar to daily injections of filgrastim 5 microgram/kg/day and was superior to the lower dose of 30 microgram/kg. A randomised phase 2 study of patients with NHL or Hodgkin's lymphoma (n = 60) further supports the safety and efficacy of pegfilgrastim.
A phase 2, randomised, double-blind study (n = 83) in patients receiving chemotherapy for de novo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim, administered during induction chemotherapy. Median time to recovery from severe neutropenia was estimated as 22 days in both treatment groups. Long term outcome was not studied.

Comparability of Ziextenzo with the reference medicine in terms of efficacy.

The efficacy of Ziextenzo has been demonstrated in double-blind, randomised, parallel-group, multi-center studies of similar design (LA-EP06-301 and LA-EP06-302). Each study was conducted in female patients with breast cancer receiving established myelosuppressive chemotherapy. Patients were randomised to either Ziextenzo or the reference product administered on Day 2 of each chemotherapy (docetaxel 75 mg/m2) in combination with doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2) cycle for up to 6 cycles. In both studies, study drug administration was 6 mg dose SC in every cycle and treatment duration was up 18 weeks.
In studies LA-EP06-301 and LA-EP06-302, the primary objective (powered at 90% for each study) was to compare Ziextenzo and the reference medicine in terms of the DSN (duration of severe neutropenia) in Cycle 1. The primary efficacy variable was defined as the mean DSN in Cycle 1. The DSN was defined as the number of consecutive days with grade 4 neutropenia (i.e. an ANC count < 0.5 x 109/L) in Cycle 1.
The results of the ANCOVA model (adjusted for the stratification factors chemotherapy and region, and the covariate baseline ANC) demonstrated that Ziextenzo is equivalent to the reference medicine because the 95% CI was contained within the defined margin of ± 1 day for both studies (Table 6 and Table 7).

5.2 Pharmacokinetic Properties

Absorption.

After a single 6 mg SC dose of pegfilgrastim in healthy subjects, the time to peak serum concentration of pegfilgrastim was variable, ranging from 4 to 60 hours with a medium value of 12 hours. After a 6 mg SC dose of pegfilgrastim in breast cancer patients receiving myelosuppressive chemotherapy, the range was from 22 to 120 hours with a median value of 24 hours. Serum concentrations of pegfilgrastim were maintained during the period of neutropenia after myelosuppressive chemotherapy.

Distribution.

The distribution of pegfilgrastim was limited to the plasma compartment.

Metabolism.

The metabolic pathway of pegfilgrastim has not been characterised.

Excretion.

The elimination of pegfilgrastim was non-linear with respect to dose; serum clearance of pegfilgrastim decreased with increasing dose. The saturable clearance pathway was attributed to neutrophils and neutrophil precursors (neutrophil-mediated, self-regulating clearance).
Results from pharmacokinetic/ pharmacodynamic modelling support neutrophil-mediated clearance as the main route of elimination (> 99%). Consistent with a self-regulating clearance mechanism, the serum concentration of pegfilgrastim declined rapidly at the onset of neutrophil recovery following myelosuppressive chemotherapy (see Figure 1).

Pharmacokinetic comparability of Ziextenzo with the reference medicine.

PK similarity of Ziextenzo was demonstrated in a single-dose, two-period crossover study in healthy subjects with a single SC administration of Ziextenzo and the reference medicine.
The assessment of PK similarity was based on the 90% CIs for the ratio of the geometric means between Ziextenzo and the reference medicine for the three primary PK parameters AUC0-inf, AUC0-last, and Cmax, which were all contained within the pre-defined PK similarity margins of 0.80 to 1.25 (Table 8).

Special populations.

Hepatic impairment.

No studies have been conducted in patients with hepatic failure; however, the pharmacokinetics of Ziextenzo are not expected to be affected by impaired hepatic function.

Renal impairment.

Renal impairment, including end-stage renal disease, appears to have no effects on the pharmacokinetics of Ziextenzo.

Elderly patients.

The pharmacokinetics of pegfilgrastim in elderly cancer patients (≥ 65 years of age) were similar to those in younger subjects.

Paediatric patients.

The safety and pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma. The mean (± Standard Deviation) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 microgram/kg was 22.0 (± 13.1) microgram.hr/mL in the 6 - 11 years age group (n = 10), 29.3 (± 23.2) microgram.hr/mL in the 12 - 21 years age group (n = 13) and 47.9 (± 22.5) microgram.hr/mL in the youngest age group (0 - 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours and 30.1 (± 38.2) hours respectively. The most common adverse reaction was bone pain.

5.3 Preclinical Safety Data

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.

No mutagenicity studies have been conducted with pegfilgrastim, although the parent protein (filgrastim) was negative in bacterial mutagenicity assays, a test for chromosome aberrations in Chinese hamster lung cells in vitro and in an in vivo mouse micronucleus test.

Carcinogenicity.

No carcinogenicity testing has been conducted for pegfilgrastim.

6 Pharmaceutical Particulars

6.1 List of Excipients

The product is formulated at pH 4.0 with 0.36 mg acetic acid, 30 mg sorbitol, 0.02 mg polysorbate 20, sodium hydroxide (if necessary for pH adjustment) in water for injection to 0.6 mL.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze). Avoid shaking. Protect from light. Ziextenzo may be exposed to room temperature (up to 35°C) for a maximum single period of up to 120 hours. Ziextenzo left at room temperature for more than 120 hours should be discarded.
Freezing should be avoided; however, if accidentally frozen, Ziextenzo should be allowed to thaw in the refrigerator before administration. If frozen a second time, Ziextenzo should be discarded.

6.5 Nature and Contents of Container

Pre filled syringe (Type I glass), with a rubber plunger stopper (bromobutyl rubber, does not contain natural rubber latex or any derivatives), a plunger rod, a stainless steel 29 gauge needle and a rubber needle cap (thermoplastic elastomer, does not contain natural rubber latex or any derivatives) with an automatic needle guard.
Each carton contains 1 ready to use pre-filled syringe with automatic needle guard containing 6 mg of pegfilgrastim in 0.6 mL (10 mg/mL) solution for SC injection.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

C849H1347N223O244S9,(C2H4O)n.

CAS number.

208265-92-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes