Consumer medicine information

Fulphila

Pegfilgrastim

BRAND INFORMATION

Brand name

Fulphila

Active ingredient

Pegfilgrastim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fulphila.

What is in this leaflet

This leaflet answers some common questions about FULPHILA.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has prescribed FULPHILA after considering its likely benefit to you, as well as the potential risks.

If you have any concerns about taking this medicine, talk to your doctor, nurse or pharmacist.

Keep this leaflet with your medicine. You may need to read this information again.

What this medicine is used for

FULPHILA is used following chemotherapy to help fight infection.

Some chemotherapy will reduce the number of neutrophils in your body. Although FULPHILA 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.

How it works

Fulphila is a long acting form of Recombinant Human Granulocyte Colony Stimulating Factor or G-CSF. Using gene technology, Fulphila 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.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

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

Before you use it

When you must not use it

Do not have FULPHILA if you have an allergy to:

  • Any medicine containing pegfilgrastim or filgrastim
  • Any of the ingredients listed at the end of this leaflet
  • Any medicines or products that are 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 FULPHILA at the same time as your chemotherapy or radiotherapy.

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

Do not use FULPHILA after the expiry date (EXP) printed on the pack.

Do not use FULPHILA if the packaging is torn or shows signs of tampering.

Do not use FULPHILA if it has been left out of the refrigerator.

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

Before you start to use it

Tell your doctor if:

  1. you have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. you are pregnant or intend to become pregnant.
Your doctor will discuss the possible risks and benefits of having FULPHILA during pregnancy.
  1. you are breastfeeding or planning to breastfeed.
Your doctor will discuss the possible risks and benefits of having FULPHILA during breastfeeding.
  1. you have, or have had:
  • a medical condition affecting the bone marrow or blood
  • a family history of rare hereditary problems of fructose intolerance. This product contains sorbitol and may not suitable in such patients
  • sickle cell disease
  • problems with your kidneys, liver, heart or other organs
  • previous treatment for cancer
  • any infections, cancers or tumours.

If you have not told your doctor about any of the above, tell them before you use FULPHILA.

Taking other medicines

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

How to use it

FULPHILA 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 FULPHILA 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 to inject FULPHILA using a pre-filled syringe with an automatic needle guard

Important

Before you use FULPHILA pre-filled syringe with automatic needle guard, read this important information:

  • It is important that you do not try to give yourself the injection unless you have received training from your doctor or healthcare provider.
  • FULPHILA is given as an injection into the tissue just under the skin (subcutaneous injection).
  • DO NOT remove the grey needle cap from the pre-filled syringe until you are ready to inject.
  • DO NOT use the pre-filled syringe if it has been dropped on a hard surface. Use a new prefilled syringe and call your doctor or healthcare provider.
  • DO NOT attempt to activate the pre-filled syringe prior to injection.
  • DO NOT attempt to remove the clear pre-filled syringe safety guard from the pre-filled syringe.
  • DO NOT attempt to remove the peelable label on the pre-filled syringe barrel before administering your injection.

Talk to your doctor or healthcare provider if you have any questions.

Guide to parts

Things to do before you inject

A. Remove the pre-filled syringe tray from the package and gather the supplies needed for your injection: alcohol wipes, a cotton ball or gauze pad, an adhesive bandage and a sharps disposal container (maybe provided).

For a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap and water.

On a clean, well-lit work surface, place the new pre-filled syringe and the other supplies.

  • DO NOT try to warm the syringe by using a heat source such as hot water or microwave
  • DO NOT leave the pre-filled syringe exposed to direct sunlight
  • DO NOT shake the pre-filled syringe
  • Keep pre-filled syringes out of the sight and reach of children

B. Open the tray, peeling away the cover. Grab the pre-filled syringe safety guard to remove the pre-filled syringe from the tray.

For safety reasons:

  • DO NOT grasp the plunger
  • DO NOT grasp the grey needle cap

C. Inspect the medicine and prefilled syringe.

  • DO NOT use the pre-filled syringe if:
The medicine is cloudy or there are particles in it. It must be a clear and colourless liquid.
Any part appears cracked or broken.
The grey needle cap is missing or not securely attached.
The expiry date printed on the label has passed the last day of the month shown.
In all cases, call your doctor or healthcare provider.

Where to inject

A. Wash hands thoroughly. Prepare and clean your injection site.

You can use:

  • Upper part of your thigh
  • Belly, except for a 5 cm (2-inch) area right around your belly button Outer area of upper arm (only if someone else is giving you the injection)

Clean the injection site with an alcohol wipe. Let your skin dry.

  • DO NOT touch the injection site before injecting
  • DO NOT inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.

B. Hold the prefilled syringe by the safety guard. Carefully pull the grey needle cap straight out and away from your body.

  • Do not twist or bend the grey needle cap.
  • Do not hold the prefilled syringe by the plunger rod.
  • Do not put the grey needle cap back onto the prefilled syringe.

C. Pinch your injection site to create a firm surface.

  • It is important to keep the skin pinched when injecting.

How to inject

A. Hold the pinch. INSERT needle into skin.

  • DO NOT touch the cleaned area of the skin

B. PUSH the plunger with slow and constant pressure until it reaches the bottom.

  • It is important that the plunger be pushed fully in order to administer your full dose.

C. RELEASE your thumb. Then LIFT the syringe off skin.

After releasing the plunger, the prefilled syringe safety guard will safely cover the injection needle.

If the guard is not activated or only partially activated, discard the product. DO NOT put the grey needle cap back on used pre-filled syringes.

When you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received the full dose. Call your healthcare provider right away.

If your injection is given by another person, he or she should also be careful when removing the needle from your skin in order to prevent accidental needle stick injury and possible infections.

How to remove detachable label

Healthcare providers only

The trade name of the administered product should be clearly recorded in the patient file.

Turn the plunger to move the label into a position where you can remove the syringe label.

Remove and save the prefilled syringe label.

Disposing

A. Discard the used pre-filled syringe and other supplies in a sharps disposal container.

Medicines should be disposed of in accordance with local requirements. Ask your pharmacist how to dispose of medicines no longer required.

These measures will help to protect the environment.

Keep the syringe and sharps disposal container out of sight and reach of children.

  • DO NOT reuse the pre-filled syringe
  • DO NOT recycle pre-filled syringes or throw them into household waste

B. Examine the injection site.

If there is blood, press a cotton ball or gauze pad on your injection site. DO NOT rub the injection site. Apply an adhesive bandage if needed.

Further information on use

How much to inject

The usual dose is one subcutaneous injection 24 hours after the end of each chemotherapy cycle.

When to inject

Use FULPHILA 24 hours after the end of each chemotherapy cycle.

Your doctor will tell you when to begin your treatment and when to stop.

If you forget your injection

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

If you inject too much (overdose)

If you inject more FULPHILA than you need, talk to your doctor, nurse or pharmacist.

If you feel unwell in any way you talk to your doctor, nurse or pharmacist immediately.

While you are using it

Things you must 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 FULPHILA.

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

Tell your doctor immediately if you become pregnant while 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 must not do

Do not use FULPHILA to treat any other complaints unless your doctor tells you to.

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

Side effects

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

All medicines can have 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 FULPHILA.

Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

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

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

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

  • 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

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

  • 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.

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

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • swelling or puffiness
  • less frequent urination
  • swelling of your stomach-area (abdomen) and feeling of fullness
  • general feeling of tiredness.

These may be serious side effects of FULPHILA. You may need urgent medical attention.

Serious side effects are rare or uncommon.

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

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

These are very serious side effects. If you have them you may have had a serious allergic reaction to FULPHILA. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything that worries you or that is making you feel unwell.

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

After using it

Storage

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

Do not freeze. Protect from light. Do not use FULPHILA if you think it has been frozen.

Keep your medicine in its pack. Protect it from light.

Keep it where children cannot reach it.

Disposal

Once you have injected FULPHILA, 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.

Product description

What it looks like

FULPHILA is a clear, colourless solution. It is supplied in a carton as a pre-filled syringe with an automatic needle guard.

Ingredients

The active ingredient in FULPHILA is 6 mg pegfilgrastim (rbe).

FULPHILA also contains:

  • sodium acetate
  • sorbitol
  • polysorbate 20
  • Water for Injections.

The grey needle cap on the pre-filled syringe with an automatic needle guard contains a derivative of latex.

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

Sponsor

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
Phone: (02) 9298 3999
www.mylan.com.au

Australian Registration Numbers:

AUST R 282830

Date of preparation

This leaflet was prepared in 17 August 2018.

Published by MIMS June 2020

BRAND INFORMATION

Brand name

Fulphila

Active ingredient

Pegfilgrastim

Schedule

S4

 

1 Name of Medicine

Fulphila is a Mylan company trade mark for pegfilgrastim (rbe), a long-acting form of recombinant human granulocyte colony-stimulating factor (G-CSF).

2 Qualitative and Quantitative Composition

Fulphila is composed of filgrastim (recombinant methionyl human G-CSF) with a 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 39,000 daltons.
Each single-use pre-filled syringe with automatic needle guard contains 6 mg of pegfilgrastim (based on protein mass only) as the active ingredient.
Fulphila (pegfilgrastim) is a biosimilar medicine to Neulasta (pegfilgrastim).
The comparability of Fulphila with Neulasta has been demonstrated with regard to physiochemical 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 Fulphila for the listed indication.

Excipients with known effect.

Sorbitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fulphila is a sterile, clear, colourless, preservative-free liquid for subcutaneous (SC) administration.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Dosage (dose and interval).

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

Method of administration.

Fulphila contains no antimicrobial agent. Fulphila 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

Fulphila 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

Identified precautions.

Splenomegaly and splenic rupture.

Very rare cases of splenic rupture, including some fatal cases, have been reported following 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 pegfilgrastim 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 pegfilgrastim, 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 breast 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.

Stevens-Johnson syndrome.

Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time.

lmmunogenicity.

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 pegfilgrastim 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.

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.

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.

See Section 5.2 Pharmacokinetic Properties.

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 haemopoietic 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 AUG), 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 foetal 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. Pegfilgrastim should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
 Whether pegfilgrastim is excreted in human milk is not known. Because many drugs are excreted in human milk, caution should be exercised if pegfilgrastim 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 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. Pegfilgrastim 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 (~0.01% and < 0.1 %) 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 Fulphila with Neulasta.

In the healthy volunteer study MYL-1401H-1001, the percentage of subjects reporting treatment related AEs was comparable between Fulphila (75%) and the reference treatments EU-Neulasta (79%) and US-Neulasta (76%). The most frequently reported treatment related PTs (i.e. reported by ≥ 20% of the subjects) were back pain and headache. There were no relevant differences in the frequency of TEAEs or percentage of subjects reporting treatment related AEs between Fulphila and the Neulasta. See Table 3.
During the exploratory study MYL-1401H-1002 in healthy volunteers to evaluate immunogenicity and safety, the safety profile of Fulphila, including immunogenicity, was similar to that of Neulasta. Summary of related TEAEs in at least 10% subjects is provided in Table 4.
In the Study MYL-1401H-3001 among patients with breast cancer, Fulphila was generally well tolerated and the safety profile was similar to EU-Neulasta. Table 5 provides a summary of related TEAEs reported by ≥ 2% of patients across all 6 cycles. The most commonly reported related TEAE by preferred term was bone pain in both Fulphila and Neulasta arm.
Overall, across the 3 clinical studies, Fulphila was generally well tolerated and the adverse events reported with Fulphila were similar to Neulasta and consistent with the clinical data of pegfilgrastim (Neulasta). The most frequently reported musculoskeletal events are likely the result of bone pain, which was expected based on the mode of action of pegfilgrastim. No serious adverse events related to Fulphila were reported.

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 13 11 26 (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.

Comparability of Fulphila with Neulasta.

Equivalence was demonstrated from the primary pharmacodynamic parameters ANC, AUC0-t and ANC Cmax when comparing Fulphila with Neulasta.
The secondary pharmacodynamic parameters ANC Tmax, CD34+ Tmax, CD34+ AUC0-t, and CD34+ Cmax were similar between Fulphila and Neulasta.

Clinical trials with Neulasta.

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 (absolute neutrophil count [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 1). 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 6). 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 every 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 Fulphila with Neulasta.

The clinical development program for Fulphila includes 3 clinical studies that were designed to confirm the similarity established at the analytical/biological and nonclinical level, address the potential for immunogenicity, and demonstrate no clinically meaningful differences between Fulphila and Neulasta.

Study MYL-1401H-1001.

This was a single-centre, randomised, double-blind, 3-period, 3-treatment, 3-way crossover study, designed to compare the pharmacokinetic (PK), pharmacodynamic (PD), safety and tolerability between Fulphila and Neulasta. A total of 216 healthy subjects were enrolled in the study, with a 2 mg SC injection being administered.

Study MYL-1401H-1002.

The second clinical study was a single-centre, randomised, open-label, 2-dose, parallel study. The primary objective of this study was to descriptively compare immunogenicity between Fulphila and Neulasta after 2 SC injections (6 mg each). The secondary objective of this study was to evaluate the safety and tolerability of Fulphila and Neulasta after 2 SC injections (6 mg each). A total of 50 healthy subjects were enrolled in this study.

Study MYL-1401H-3001.

The third clinical study carried out was Study MYL-1401H-3001, which was a multi-centre, randomised, double-blind, parallel-group study with 2 treatment groups designed to evaluate the efficacy and safety of Fulphila versus Neulasta in patients (194 adults; 127 in Fulphila and 67 in Neulasta group) with newly diagnosed Stage II/III breast cancer receiving up to 6 cycles of TAC anti-cancer therapy.
The primary objective of this study was to compare the efficacy of Fulphila and Neulasta for the prophylactic treatment of chemotherapy-induced neutropenia in patients with Stage II/III breast cancer receiving TAC anti-cancer chemotherapy. The secondary objectives included: to assess the safety of Fulphila and Neulasta when administered through 6 cycles of TAC anti-cancer chemotherapy; and to assess the potential immunogenicity of Fulphila and Neulasta during chemotherapy and up to 24 weeks following the first administration of pegfilgrastim.

Summary.

For patients who were treated with either Fulphila or Neulasta (whether sourced from the EU or the US), PK and PD parameters, as well as immunogenicity response, were similar across the 3 sources of pegfilgrastim.
Fulphila demonstrated equivalent efficacy to Neulasta in the prophylactic treatment of chemotherapy-induced neutropenia in patients with breast cancer. For patients who were treated with either Fulphila or Neulasta, results were comparable for duration of severe neutropenia (DSN) in Cycle 1. The mean (± SD) DSN in the Fulphila arm was 1.2 (± 0.93), compared to 1.2 (± 1.10) in the EU-Neulasta group, and the LS mean difference was 0.01 (SE 0.148). The 95% CI (-0.285, 0.298) for the difference in LS Mean DSN of Fulphila and EU-Neulasta was within the pre-specified equivalence range of [-1 day, +1 day]. The secondary efficacy endpoints showed similar results for Fulphila or Neulasta. In Cycle 1, 5/127 (3.9%) patients had febrile neutropenia in the Fulphila group and 1/67 (1.5%) patient in the EU-Neulasta group. However, only 3(2.4%) patients in the Fulphila group had confirmed FN as per ESMO definition and other patients had insufficient information but were conservatively included as febrile neutropenia. The lower FN rates seen in study MYL-1401H-3001 versus literature especially in EU-Neulasta arm was due to limited sample size and unequal randomization. All the FN were of short duration, recovered between 3-6 days of onset, without infections requiring treatment, not requiring rescue therapy with filgrastim and no infection-related mortality. Overall, 5 (3.9%) patients in the MYL-1401H group and 1 (1.5%) patient in the EU-Neulasta group had their chemotherapy doses reduced, omitted, or delayed. The cause of this was neutropenia in 2 (1.6%) patients and FN in 3 (2.4%) patients in Fulphila group and FN in 1 (1.5%) patient in the EU-Neulasta group. There were no changes to the chemotherapy doses due to documented infections. The safety profile, including immunogenicity, was similar to that of Neulasta.
Fulphila was generally well tolerated, there were no new safety concerns identified, similar number of patients showed ADA, and there was an overall low rate of ADA and NAb.
Overall, Fulphila was bioequivalent to Neulasta. The clinical data confirm the high similarity established at the physiochemical/biological and nonclinical levels and demonstrate no clinically meaningful differences between Fulphila and Neulasta to complete the totality of evidence in support of biosimilarity.

5.2 Pharmacokinetic Properties

Absorption.

After a single SC dose of pegfilgrastim in man, the time to peak serum concentration of pegfilgrastim was variable, ranging from 8 to 120 hours. After a 6 mg SC dose, the range was from 15.9 to 120.5 hours with a median value of 39.9 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).

Special populations.

Impaired hepatic function.

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

Impaired renal function.

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

Elderly patients.

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

Paediatric.

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.

Comparability of Fulphila with Neulasta.

Bioequivalence was demonstrated for the primary pharmacokinetic parameters Cmax and AUC0-inf of PEG-GCSF when comparing Fulphila with Neulasta.
The secondary pharmacokinetic parameters AUC0-t, Tmax, kel, Vd/F and t1/2 of PEG-GCSF were similar between Fulphila and Neulasta.

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.
Fulphila contains 30 mg sorbitol per syringe. This should be taken into consideration in patients with rare hereditary problems of fructose intolerance and may not be suitable in such patients.

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 and it also contains the following inactive ingredients, sorbitol, polysorbate 20, acetate (as acetic acid), sodium (as sodium hydroxide) and water for injection.

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.

6.5 Nature and Contents of Container

Each Fulphila carton contains 1 ready to use pre-filled glass syringe with automatic needle guard containing 6 mg of pegfilgrastim in 0.6 mL (10 mg/mL) solution for SC injection.
Container type: Glass Type I Clear.
Pack sizes: 1.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


Structure of pegfilgastrim and amino acid sequence (see Figure 2):

Chemical name.

N-(3-hydroxypropyl) methionyl colony-stimulating factor (human), 1-ether with α-methyl-ω-hydroxypoly (oxyethylene).

Molecular formula.

(C2H4O)nC845H1339N223O243S9.

Molecular weight.

~ 39 kDa.

CAS number.

CAS Registry Number: 208265-92-3.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes