Consumer medicine information

Lonquex

Lipegfilgrastim

BRAND INFORMATION

Brand name

Lonquex Solution for injection

Active ingredient

Lipegfilgrastim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lonquex.

What is in this booklet

This booklet answers some common questions about Lonquex.

Please note that this booklet does not contain everything there is to know about Lonquex. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has prescribed Lonquex 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 booklet with your medicine.

You may need to read this information again.

What is Lonquex used for

Lonquex is used following chemotherapy to help fight infection.

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

Lonquex contains the active substance lipegfilgrastim. Lipegfilgrastim is a long-acting modified protein produced by biotechnology in bacteria called Escherichia coli. It belongs to a group of proteins called cytokines and is similar to a natural protein (granulocyte-colony stimulating factor [G-CSF]) produced by your own body.

Lipegfilgrastim stimulates the bone narrow (the tissue where new blood cells are made) to produce more white blood cells. White blood cells are important as they help your body fight infection. These cells are very sensitive to the effects of chemotherapy which can cause the number of these cells in your body to decrease. If white blood cells fall to a low level, there may not be enough left in the body to fight bacteria and you may have an increased risk of infection.

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 Lonquex if you have allergies to:

  • Lipegfilgrastim or any other medicines like this one (i.e. filgrastim, lenograstim or
  • pegfilgrastim of the group of G-CSFs).
  • certain sugars
  • This medicine contains sorbitol.
  • This medicine contains less than 1 mmol (23 mg) sodium per prefilled syringe, i.e. essentially 'sodium-free'

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.

Before you start to use it

Tell your doctor if

  1. you have sickle cell anaemia, which is an inherited disease characterized by sickle-shaped red blood cells.
  2. you have a cough, fever and difficulty breathing.
    It could be a consequence of a pulmonary disorder.
  3. you have upper abdominal pain or pain at the tip of your shoulder.
    It could be a consequence of a spleen disorder.
  4. you are pregnant or intend to become pregnant.
    Lonquex has not been tested in pregnant women. It is important that you tell your doctor if you are pregnant, think you may be pregnant or are planning to have a baby, as the doctor may decide that you should not use this medicine.
  5. you are breast-feeding.
    It is unknown whether the active substance in this medicine passes into the breast milk. You should therefore interrupt breast-feeding during treatment.
  6. If you have not told your doctor about any of these things, tell him/her before you use Lonquex.

How to use it

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

It is important that you do not try to give yourself the injection unless you have received special training from your doctor or nurse.

If you are not sure about giving yourself the injection or you have any questions, please ask your doctor or nurse for help.

The recommended dose is one prefilled syringe (6 mg lipegfilgrastim) ONCE PER CHEMOTHERAPY CYCLE. This medicine should be given approximately 24 hours after your last dose of chemotherapy at the end of each chemotherapy cycle.

To give yourself an injection into the tissue under the skin you will need:

  • a pre-filled syringe of Lonquex
  • an alcohol wipe
  • a piece of gauze bandage or sterile gauze swab

Instructions for Injecting Lonquex

What you should do before your injection:

  • Take the medicine out of the refrigerator.
  • Open the blister and take the pre-filled syringe out of the blister (see picture 1). Do not pick up the pre-filled syringe by the plunger or needle cover. This will damage the safety device.
  • Check the expiry date on the pre-filled syringe label (EXP). Do not use if the date has passed the last day of the month shown.
  • Check the appearance of Lonquex. It must be a clear and colorless liquid. If there are particles in it or if it is cloudy, you must not use it.
  • Do not shake Lonquex vigorously as this may affect its activity.
  • For a more comfortable injection, let the pre-filled injection stand for 30 minutes to reach room temperature (not above 25°C) or hold the prefilled syringe gently in your hand for a few minutes. Do not warm Lonquex in any other way (for example, do NOT warm it in a microwave or in hot water).
  • Do NOT remove the needle cover from the syringe until you are ready to inject.
  • Find a comfortable, well-lit place. Place everything where you can reach for it (the Lonquex pre-filled syringe, an alcohol wipe and a piece of gauze bandage or a sterile gauze swab).
  • Wash your hands thoroughly.

How to prepare for your injection

Before you give yourself a Lonquex injection, you must do the following:

  • Hold the syringe and gently remove the cover from the needle without twisting. Pull straight as shown in pictures 2 and 3. Do not touch the needle or push the plunger.
  • You may notice small air bubbles in the pre-filled syringe. If there are air bubbles present, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. With the syringe pointing upwards, expel all air form the syringe by pushing the plunger slowly upwards.
  • You can now use the pre-filled syringe.
  • Keep pre-filled syringes out of the sight and reach of children.

Where your injection should be given

The most suitable places to inject yourself are:

  • the top of your thighs.
  • the abdomen (see grey areas in picture 4)avoiding the skin directly surrounding the navel.
  • If someone else is injecting you, they can also use the back and side of your upper arms (see grey areas in pictures 5 and 6).

How you should inject yourself

  • Disinfect the injection site on the skin by using an alcohol wipe and pinch the skin between your thumb and forefinger, without squeezing it (see picture 7).
  • Put the needle fully into the skin as shown by your nurse or doctor. The angle between the syringe and skin should not be too narrow (at least 45°, see picture 8).
  • Pull slightly on the plunger to check that a blood vessel has not been punctured. If you see blood in the syringe, remove the needle and re-insert it in another place.
  • Inject the liquid into the tissue slowly and evenly, always keeping your skin pinched (see picture 9).
  • Push the plunger as far as it will go to inject all the liquid. While the plunger is still pressed all the way down, remove the needle from the skin (see picture 10). Then release the plunger. The safety device will be activated immediately. The entire needle and syringe will be drawn back automatically and covered so that you cannot prick yourself (see picture 11).
  • Press the injection site with a piece of gauze bandage or a sterile gauze swab for several seconds.
  • Each pre-filled syringe is for single use only.

If you have any problems, please ask your doctor or pharmacist for help and advice.

How you should dispose of used syringes

  • Do not put the cover back on used needles.
  • Put used syringes into the puncture-proof container and keep this container out of the sight and reach of children.
  • Dispose of the full puncture-proof container as instructed by your doctor, nurse or pharmacist.
  • Never put the syringes that you have used back into your normal household rubbish bin.

Further general information

How much to inject

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

When to inject

Lonquex should be injected 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, advise your doctor, nurse or pharmacist as soon as possible about your missed dose.

If you inject too much (overdose)

If you inject more Lonquex than you need, you should contact your doctor, nurse or pharmacist. If you feel unwell in any way you should contact your doctor, nurse or pharmacist immediately.

While you are using it

Things you must do

Be alert for any signs or symptoms of infection.

There are many ways an infection may show itself.

You should watch for:

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

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

Tell your doctor, nurse and pharmacist that you are using Lonquex if you are about to be started on any new medicine.

Tell any other doctors 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.

Things you must not do

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

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

Side Effects

Tell your doctor as soon as possible

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

Like all medicines, this medicine can cause side effects, although you may not experience any of them.

Do not be alarmed by this list of possible side effects.

Most serious side effects

  • Allergic reactions such as skin rash, raised itchy areas of skin and serious allergic reactions with weakness, drop in blood pressure, difficulty breathing and swelling of the face have been reported uncommonly (may affect up to 1 in 100 people). If you think you are having this type of reaction, you must stop your Lonquex injection and get medical help immediately.
  • Increased spleen size and cases of spleen ruptures have been reported with other medicines similar to Lonquex. Some cases of splenic rupture were fatal. It is important to contact your doctor immediately if you experience pain in the upper left side of the abdomen or left shoulder pain since this may relate to a problem with your spleen.
  • Cough, fever and difficult or painful breathing can be signs of uncommon (may affect up to 1 in 100 people) serious pulmonary side effects, such as pneumonia and acute respiratory distress syndrome, which may be fatal. If you have a fever or any of these symptoms, it is important to contact your doctor immediately.
  • It is important to contact your doctor immediately if you have any of the following symptoms: swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. These symptoms generally develop in a rapid fashion. These could be symptoms of a condition reported with other medicines similar to Lonquex called "capillary leak syndrome", which causes blood to leak from the small blood vessels into your body and needs urgent medical attention.

Other side effects

Very common (may affect more than 1 in 10 people):

  • Musculoskeletal pains such as bone pain and pain in the joints, muscles, limbs, chest, neck or back. Your doctor will tell you what you can take to ease the bone pain.

Common (may affect up to 1 in 10 people):

  • Reduction in blood platelets, which increases risk of bleeding or bruising
  • Headache
  • Skin reactions, such as redness or rash
  • Low blood levels of potassium, which can cause muscle weakness, twitching or abnormal heart rhythm
  • Chest pain

Uncommon (may affect up to 1 in 100 people):

  • Rise in white blood cells
  • Local reactions at the injection site, such as pain or hardening
  • Some changes may occur in your blood, but these will be detected by routine blood tests.

Side effects that have been seen with similar medicines, but not yet with Lonquex

  • Sickle cell crises in patients with sickle cell anaemia
  • Plum-colored raised painful sores on the limbs and sometimes the face and neck with fever (Sweet's syndrome)
  • Inflammation of the blood vessels in the skin

If you get any side effects, talk to your doctor, pharmacist or nurse. This also includes any possible side effects not listed above. Tell your doctor if you notice anything that worries you or that is making you feel unwell.

After using it

Storage

  • Keep Lonquex in a refrigerator at a temperature of 2°C to 8°C.
  • Do not freeze.
  • Lonquex may be removed from the refrigerator and stored below 25°C for a maximum single period of up to 3 days. Once removed from the refrigerator, the medicine must be used within this period or disposed of.
  • Keep the pre-filled syringe in the outer carton, in order to protect from light.
  • Do not use this medicine if you notice that it is cloudy or there are particles in it.
  • Do not use this medicine after the expiry date which is stated on the outer carton and on the label of the pre-filled syringe after EXP. The expiry date refers to the last day of that month.
  • Keep Lonquex out of the sight and reach of children.
  • Dispose this medicine as instructed by your doctor, nurse or pharmacist

Disposal

Once you have injected Lonquex, 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

Lonquex is a solution for injection (injection) in a pre-filled syringe with a fixed injection needle in a blister. Lonquex is a clear and colorless solution. Each prefilled syringe contains 0.6 mL solution.

Each pack contains 1 pre-filled syringe with or without safety device.

Ingredients

The active ingredient in Lonquex is lipegfilgrastim.

Other ingredients are:

  • glacial acetic acid
  • sodium hydroxide
  • sorbitol
  • polysorbate 20
  • water for injection

Supplier

Teva Pharma Australia Pty Ltd
Level 2, 37 Epping Road
Macquarie Park
NSW 2113
Australia
Toll Free number: 1800 288 382

Australian Registration Number: AUST R 231016

This leaflet was prepared in November 2015.

® Registered trademark

BRAND INFORMATION

Brand name

Lonquex Solution for injection

Active ingredient

Lipegfilgrastim

Schedule

S4

 

1 Name of Medicine

Lipegfilgrastim.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1117844-87-7.

2 Qualitative and Quantitative Composition

Lonquex is the Teva Pharmaceuticals Ltd. trademark for lipegfilgrastim (rbe), a long acting form of recombinant human granulocyte colony stimulating factor (G-CSF).
Lonquex contains the active substance lipegfilgrastim (rbe). Lipegfilgrastim is a covalent conjugate of a 19,000 dalton E. coli produced r-metHuG-CSF and a 20,000 dalton polyethylene glycol (PEG) moiety. The theoretical molecular mass of r-metHuG-CSF is 18,798.9 dalton. The molecular mass of the final glycoPEGylated human N-methionyl granulocyte-colony stimulating factor is approximately 39,000 dalton. The PEG moiety is attached enzymatically through a glycolinker (glycyl-sialyl-GalNac) to the amino acid Thr134 (which corresponds to the glycosylation site Thr133 in endogenous G-CSF).
Lipegfilgrastim is a covalent conjugate of filgrastim with a single methoxy polyethylene glycol (PEG) molecule via a carbohydrate linker consisting of L-glycine, N-acetylneuraminic acid (sialic acid) and a N-acetylgalactosamine (GalNAc) moiety to Threonine134. The average molecular mass is approximately 39,000 Da of which the protein moiety constitutes approximately 48%.
The potency of this medicinal product should not be compared to the potency of another pegylated or nonpegylated protein of the same therapeutic class. For more information, see Section 5 Pharmacological Properties.
Each single use pre-filled syringe of Lonquex contains 6 mg of lipegfilgrastim in 0.6 mL solution. Each mL of solution for injection contains 10 mg of lipegfilgrastim.
This medicinal product contains 30 mg sorbitol per pre-filled syringe. Patients with rare hereditary problems of fructose intolerance should not use this medicinal product.
This medicinal product contains less than 1 mmol sodium (0.14 mg) per pre-filled syringe, i.e. essentially 'sodium-free'.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Lonquex is a sterile, clear, colourless, preservative free aqueous liquid for subcutaneous (SC) administration, presented in a 1 mL prefilled syringe.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: immunostimulants, colony stimulating factors, ATC code: L03AA14.

Mechanism of action.

Human G-CSF is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. Filgrastim is an unglycosylated recombinant methionyl human G-CSF. Lipegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Lipegfilgrastim binds to human the G-CSF receptor like filgrastim and pegfilgrastim.

Pharmacodynamics effects.

Lipegfilgrastim and filgrastim induced a marked increase in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or lymphocytes. These results suggest that the G-CSF moiety of lipegfilgrastim confers the expected activity of this growth factor: stimulation of proliferation of haematopoietic progenitor cells, differentiation into mature cells and release into the peripheral blood. This effect includes not only the neutrophil lineage but extends to other single lineage and multilineage progenitors and pluripotent haematopoietic stem cells. G-CSF also increases the antibacterial activities of neutrophils including the phagocytosis.

Clinical trials.

Clinical efficacy and safety.

Once per cycle dosing of Lonquex was investigated in two pivotal randomised, double blind clinical studies in patients undergoing myelosuppressive chemotherapy.
The first pivotal (phase III) clinical study XM22-03 was an active controlled study in 202 patients with stage II-IV breast cancer receiving up to 4 cycles of chemotherapy consisting of doxorubicin and docetaxel. Patients were randomised 1:1 to receive 6 mg Lonquex or 6 mg pegfilgrastim. The study showed noninferiority of 6 mg Lonquex to 6 mg pegfilgrastim for the primary endpoint, duration of severe neutropenia (DSN) in the first cycle of chemotherapy (see Table 4).
The second pivotal (phase III) clinical study XM22-04 was a placebo controlled study in 375 patients with non-small cell lung cancer receiving up to 4 cycles of chemotherapy consisting of cisplatin and etoposide. Patients were randomised 2:1 to receive either 6 mg Lonquex or placebo. The results of the study are presented in Table 5. When the main study was finalised, the incidence of death was 7.2% (placebo) and 12.5% (6 mg Lonquex) although after the 360 day follow-up period the overall incidence of death was similar between placebo and Lonquex (44.8% and 44.0%; safety population).

Immunogenicity.

An analysis of antidrug antibodies of 579 patients and healthy volunteers treated with lipegfilgrastim, 188 patients and healthy volunteers treated with pegfilgrastim and 121 patients treated with placebo was performed. Drug specific antibodies emerging after start of treatment were detected in 0.86% of the subjects receiving lipegfilgrastim, in 1.06% of the subjects receiving pegfilgrastim and in 1.65% of the subjects receiving placebo. No neutralising antibodies against lipegfilgrastim were observed.

5.2 Pharmacokinetic Properties

Absorption.

Following initial sc administration of lipegfilgrastim in healthy subjects, a lag in absorption of approximately 1 hour is observed with maximum serum concentrations being attained at approximately 35 hours after dose administration. Given its molecular weight, lipegfilgrastim is believed to be primarily absorbed via the lymphatic system then drained into the vascular system.
Following repeated administration in patients (cycle 4), mean serum concentrations of lipegfilgrastim are consistently lower than after a single dose. Maximum serum concentrations after repeat doses were attained earlier (8 to 24 hours after dose administration) than after a single dose. The observed differences in pharmacokinetics following repeated administrations of lipegfilgrastim are consistent with the presence of higher absolute neutrophil count (ANC).

Distribution.

Lipegfilgrastim has a small, weight dependent volume of distribution (Vc approximately 70 mL/kg), indicating that it is not distributed beyond the lymphatic/ vascular system.

Metabolism.

Lipegfilgrastim is metabolised via intracellular or extracellular degradation by proteolytic enzymes. Following binding to the G-CSF receptors, intracellular degradation occurs with lipegfilgrastim being internalised by neutrophils (nonlinear process), then degraded within the cell by endogenous proteolytic enzymes. A second, linear pathway, is likely due to extracellular protein degradation by neutrophil elastase and other plasma proteases.

Excretion.

Lipegfilgrastim has two distinct clearance pathways. The first clearance pathway is linear and is likely comprised of degradation by proteolytic enzymes. The second pathway is nonlinear neutrophil mediated clearance (intracellular) that is dependent on ANC.
After administration of lipegfilgrastim, the nonlinear clearance in any given subject varies over time together with the ANC values and the drug concentration values. In general, low ANC values are associated with a high linear clearance percentage. Thus, at lower ANC values the linear clearance is the predominant pathway and at high ANC values nonlinear clearance predominates. Given the differences in ANC values between healthy subject and cancer patients, who are exposed to the effects of myelosuppressive CTX, the predominant pathway varies between populations. Of note, the predominant pathway appears to change from linear to nonlinear at an ANC value of approximately ≥ 5-10 cells x 109/L.
Median terminal half-life of lipegfilgrastim is approximately 33 hours and median MRT is approximately 58 hours.
Of note, the PEG moiety which is cleaved from the amino acid backbone of the molecule via internal and external degradation is likely excreted unchanged in the urine due to its molecular size.

Healthy volunteers.

In 3 studies (XM22-01, XM22-05, XM22-06) in healthy volunteers, the maximum blood concentration was reached after a median of 30 to 36 hours and the average terminal half-life ranged from approximately 32 to 62 hours after a single subcutaneous injection of 6 mg lipegfilgrastim.
After subcutaneous injection of 6 mg lipegfilgrastim at three different sites (upper arm, abdomen and thigh) in healthy volunteers, the bioavailability (peak concentration and area under the curve (AUC)) was lower after subcutaneous injection in the thigh compared to subcutaneous injection in the abdomen and in the upper arm. In this limited study XM22-06, bioavailability of lipegfilgrastim and observed differences among the injection sites were higher in male subjects compared to female subjects. Nevertheless, pharmacodynamic effects were similar and independent from gender and injection site.

Special populations.

Cancer patients.

In 2 studies (XM22-02 and XM22-03) in patients with breast cancer receiving chemotherapy consisting of doxorubicin and docetaxel, mean maximum blood concentrations of 227 and 262 nanogram/mL were reached after median times to maximum concentration (tmax) of 44 and 48 hours. The mean terminal half-lives were approximately 29 and 31 hours after a single subcutaneous injection of 6 mg lipegfilgrastim during the first cycle of chemotherapy. After a single subcutaneous injection of 6 mg lipegfilgrastim during the fourth cycle, the maximum blood concentrations were lower than observed in the first cycle (mean values 77 and 111 nanogram/mL) and were reached after median tmax of 8 hours. The mean terminal half-lives in the fourth cycle were approximately 39 and 42 hours.
In a study (XM22-04) in patients with non-small cell lung cancer receiving chemotherapy consisting of cisplatin and etoposide, the mean maximum blood concentration of 317 nanogram/mL was reached after a median tmax of 24 hours and the mean terminal half-life was approximately 28 hours after a single subcutaneous injection of 6 mg lipegfilgrastim during the first cycle of chemotherapy. After a single subcutaneous injection of 6 mg lipegfilgrastim during the fourth cycle, the mean maximum blood concentration of 149 nanogram/mL was reached after a median tmax of 8 hours and the mean terminal half-life was approximately 34 hours.
Lipegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, which becomes saturated at higher doses. Consistent with a self regulating clearance mechanism, the serum concentration of lipegfilgrastim declines slowly during the chemotherapy induced transient neutrophil nadir and rapidly at the following onset of neutrophil recovery (see Figure 1).

Patients with renal or hepatic impairment.

There was no meaningful effect of mild renal impairment (CrCL: 62-87 mL/min; n = 20) on the pharmacokinetics of lipegfilgrastim in cancer patients. The impact of more severe renal impairment on the pharmacokinetics of lipegfilgrastim was not studied.
The impact of hepatic impairment on the pharmacokinetics of lipegfilgrastim in cancer patients was not studied.
Due to the neutrophil mediated clearance mechanism, the pharmacokinetics of lipegfilgrastim is not expected to be affected by renal or hepatic impairment.

Elderly patients.

Limited patient data indicate that the pharmacokinetics of lipegfilgrastim in elderly patients (65-74 years) is similar to that in younger patients. No pharmacokinetic data are available in patients ≥ 75 years.

Gender.

No statistically significant differences in exposure were observed between men and women.

Race.

Due to the limited data in the population studied, conclusions regarding the impact of race on the pharmacokinetics of lipegfilgrastim cannot be drawn.

Effect of body weight.

A statistically significant difference in lipegfilgrastim exposure was observed between the heaviest (> 80 kg) and the lightest (< 60 kg) subjects studied. Exposure in the heaviest subjects was approximately 30% that of the exposure in lightest subjects. A decrease in efficacy cannot be excluded in patients > 80 kg from currently available data.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies were not performed with Lonquex.
Recombination products such as Lonquex would not be expected to interact directly with deoxyribonucleic acid (DNA) or other chromosomal material. A mutagenic potential is not expected for Lonquex.
The mutagenic potential of r-metHuG-CSF (filgrastim, Neupogen) was evaluated in vivo (mouse micronucleus test, intraperitoneal administration) as well as in vitro (Ames test, chromosomal aberration test). r-metHuG-CSF was found not to be mutagenic.

Carcinogenicity.

Carcinogenicity studies with Lonquex were not performed as there is no evidence for a genotoxic effect of these cytokines and although not being relevant for chronic toxicity studies in rats, during long-term administration carcinogenicity studies neutralising antibodies with G-CSF may develop and may restrict a meaningful result.
Moreover, cytotoxic chemotherapy as concomitant therapy of Lonquex in patients with cancer implies a genotoxic and carcinogenic risk that cannot be separated from potential effects of Lonquex.
There is no indication for a potential carcinogenicity of Lonquex from chronic toxicity studies.

4 Clinical Particulars

4.1 Therapeutic Indications

Lonquex is indicated for reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

4.3 Contraindications

Lonquex is contraindicated in patients with known hypersensitivity to lipegfilgrastim and any other component of the product or other G-CSF products including lenograstim, pegfilgrastim and filgrastim.

4.4 Special Warnings and Precautions for Use

General.

The safety and efficacy of Lonquex have not been investigated in patients receiving high dose chemotherapy. Lonquex should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage regimens.
In order to improve the traceability, the trade name and batch number of the administered medicinal product should be clearly recorded in the patient file.

Allergic reactions and immunogenicity.

Patients who are hypersensitive to G-CSF or derivatives are also at risk of hypersensitivity reactions to lipegfilgrastim due to possible crossreactivity. No lipegfilgrastim therapy should be commenced in these patients because of the risk of cross reaction.
Most biological medicinal products elicit some level of antidrug antibody response. This antibody response can, in some cases, lead to undesirable effects or loss of efficacy. If a patient fails to respond to treatment, the patient should undergo further evaluation.
If a serious allergic reaction occurs, appropriate therapy with close patient follow-up over several days should be administered.

Haematopoietic system.

Treatment with lipegfilgrastim does not preclude thrombocytopenia and anaemia caused by myelosuppressive chemotherapy. Lipegfilgrastim may also cause reversible thrombocytopenia (see Section 4.8 Adverse Effects (Undesirable Effects)). Regular monitoring of the platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products that are known to cause severe thrombocytopenia.
Leukocytosis may occur (see Section 4.8 Adverse Effects (Undesirable Effects)). No adverse events directly attributable to leukocytosis have been reported. Elevation in white blood cells (WBC) is consistent with the pharmacodynamics effects of lipegfilgrastim. A WBC count should be performed at regular intervals during therapy owing to the clinical effects of lipegfilgrastim and the potential for leukocytosis. If WBC counts exceed 50 x 109/L after the expected nadir, lipegfilgrastim should be discontinued immediately.
Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging findings. This should be considered when interpreting bone imaging results.

Patients with myeloid leukaemia or myelodysplastic syndromes.

Granulocyte colony stimulating factor can promote growth of myeloid cells and some nonmyeloid cells in vitro.
The safety and efficacy of Lonquex have not been investigated in patients with chronic myeloid leukaemia, myelodysplastic syndromes or secondary acute myeloid leukaemia; it should therefore not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from acute myeloid leukaemia.

Splenic adverse reactions.

Frequent but generally asymptomatic cases of splenomegaly and infrequent cases of splenic rupture, including fatal cases, have been reported after administration of G-CSF or derivatives (see Section 4.8 Adverse Effects (Undesirable Effects)). Spleen size should therefore be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture or enlarged spleen should be considered in patients reporting left upper abdominal pain or shoulder tip pain.

Pulmonary adverse reactions.

Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after administration of lipegfilgrastim (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk.

Adult respiratory distress syndrome (ARDS).

The onset of pulmonary symptoms such as cough, fever and dyspnoea in association with radiological signs of pulmonary infiltrates and deterioration in pulmonary function together with an increased neutrophil count may be preliminary signs of acute respiratory distress syndrome (ARDS) (see Section 4.8 Adverse Effects (Undesirable Effects)). In such circumstances Lonquex should be discontinued at the discretion of the physician and appropriate treatment given.

Pulmonary haemorrhage and haemoptysis.

Pulmonary haemorrhage manifesting as pulmonary infiltrates and haemoptysis requiring hospitalization have been reported in patients and donors receiving human G-CSF. Haemoptysis resolved with discontinuation of human G-CSF.

Vascular adverse reactions.

Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The symptoms experienced include fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by CT scan and generally resolved after withdrawal of G-CSF.
Capillary leak syndrome has been reported after administration of G-CSF or derivatives and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate symptomatic treatment, which may include a need for intensive care (see Section 4.8 Adverse Effects (Undesirable Effects)).

Glomerulonephritis.

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

Patients with sickle cell anaemia.

Sickle cell crisis has been associated with the use of G-CSF or derivatives in patients with sickle cell anaemia. Physicians should therefore exercise caution when administering Lonquex in patients with sickle cell anaemia, monitor appropriate clinical parameters and laboratory results and be attentive to the possible association of lipegfilgrastim with splenic enlargement and vaso-occlusive crisis.

Hypokalaemia.

Hypokalaemia may occur (see Section 4.8 Adverse Effects (Undesirable Effects)). For patients with increased risk on hypokalaemia due to underling disease or comedications, it is recommended to monitor the serum potassium level carefully and to substitute potassium if necessary.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Special populations.

Use in the elderly.

Of the 399 patients treated with lipegfilgrastim 6 mg in the cancer studies, 69 (17.3%) were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Paediatric use.

The safety and efficacy of Lonquex in children and adolescents aged less than 18 years have not yet been established.

Effects on laboratory tests.

No data are available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal clinical drug interaction studies between lipegfilgrastim and other drugs have been performed.
In vitro data indicate that lipegfilgrastim has little or no direct or immune system-mediated effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 activity.
Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, Lonquex should be administered approximately 24 hours after administration of cytotoxic chemotherapy. Concomitant use of lipegfilgrastim with any chemotherapeutic medicinal product has not been evaluated in patients. In animal models, concomitant administration of G-CSF and 5-fluorouracil (5-FU) or other antimetabolites has been shown to potentiate myelosuppression.
The safety and efficacy of Lonquex have not been evaluated in patients receiving chemotherapy associated with delayed myelosuppression, e.g. nitrosoureas.
The safety and efficacy of Lonquex have not been evaluated in patients receiving radiotherapy.
The potential for interaction with lithium, which also promotes the release of neutrophils, has not been specifically investigated and should be used with caution. There is no evidence that such an interaction would be harmful.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data are available. Animal studies with G-CSF and derivatives do not indicate harmful effects with respect to fertility.
(Category B3)
There are very limited data (less than 300 pregnancy outcomes) on the use of lipegfilgrastim in pregnant women. Animal studies have shown reproductive toxicity. Lonquex has not been studied in pregnant women and should not be used during pregnancy until further evidence is available.
In a study of toxicity to reproduction and development in rabbits, an increased incidence of postimplantation loss and abortion has been observed at high doses of lipegfilgrastim, likely owing to an exaggerated pharmacodynamic effect specific for rabbits. There is no evidence that lipegfilgrastim is teratogenic. These findings are consistent with results from G-CSF and derivatives. Published information on G-CSF and derivatives reveal no evidence of adverse effects on fertility and embryofoetal development in rats or prenatal/ postnatal effects other than those related to maternal toxicity as well. There is evidence that filgrastim and pegfilgrastim may be transported at low levels over the placenta in rats, although no information is available for lipegfilgrastim. The relevance of these findings for humans is not known.
Lonquex has not been studied in lactating women and should not be used while breastfeeding until further evidence is available.

4.8 Adverse Effects (Undesirable Effects)

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.

Summary of the safety profile.

The most frequent undesirable effects are musculoskeletal pains. Musculoskeletal pains are generally of mild to moderate severity, transient and can be controlled in most patients with standard analgesics.
Capillary leak syndrome, which can be life threatening if treatment is delayed, has been reported mostly in cancer patients undergoing chemotherapy after administration of G-CSF or derivatives.

Adverse events in clinical studies.

The following event data in Table 1 compares the frequency of treatment emergent adverse events for Lonquex 6 mg (target dose) and the active control, pegfilgrastim 6 mg, in patients with breast cancer. Table 2 compares the frequency of treatment emergent adverse events for Lonquex 6 mg and placebo in patients with non-small cell lung cancer (NSCLC).

Tabulated list of adverse reactions.

The safety of lipegfilgrastim has been evaluated based on results from clinical studies including 506 patients and 76 healthy volunteers treated at least once with lipegfilgrastim.
The adverse reactions listed in Table 3 are classified according to System organ class. Frequency groupings are defined according to the following convention: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000; not known: cannot be estimated from the available data.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Post-marketing experience.

Adverse reactions reported during the postmarketing period are derived from spontaneous reports including reports from healthcare professionals, consumers, competent authorities and from solicited case reports including those from noninterventional studies.
Among adverse reactions reported postmarketing, the majority of reported ADRs belonged to SOC musculoskeletal and connective tissue disorders and blood and lymphatic system disorders.
A review of these case reports does not demonstrate any new events of interest or potential safety signals, no new relevant postmarketing safety information was identified to alter the known benefit-risk profile of Lonquex.

Description of selected adverse reactions.

Cases of pulmonary haemorrhage and haemoptysis have been reported in post-marketing experience after administration of G-CSF.
Thrombocytopenia and leukocytosis have been reported.
Hypersensitivity reactions such as allergic skin reactions, urticaria, angioedema and serious allergic reactions may occur.
Hypokalaemia has been reported.
Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported. These pulmonary adverse reactions may also include pulmonary oedema, pulmonary infiltrates, pulmonary fibrosis, respiratory failure or ARDS.
Skin reactions such as erythema and rash may occur.
Injection site reactions such as injection site induration and injection site pain may occur.
The most frequent adverse reactions are musculoskeletal pains such as bone pain and myalgia. Musculoskeletal pains are generally of mild to moderate severity, transient and can be controlled in most patients with standard analgesics.
Reversible, mild to moderate elevations in alkaline phosphatase and lactate dehydrogenase may occur, with no associated clinical effects. Elevations in alkaline phosphatase and lactate dehydrogenase most likely originate from the increase in neutrophils.
Certain adverse reactions have not yet been observed with lipegfilgrastim, but are generally accepted as being attributable to G-CSF and derivatives:

Blood and lymphatic system disorders.

Splenic rupture including some fatal cases; sickle cell crisis in patients with sickle cell anaemia.

Vascular disorders.

Capillary leak syndrome: Cases of capillary leak syndrome have been reported in postmarketing experience after administration of G-CSF or derivatives. These have generally occurred in patients suffering from advanced malignant diseases, having sepsis, taking multiple chemotherapy medications or undergoing apheresis.
Aortitis: Rare cases of aortitis have been reported in post-marketing experience after administration of G-CSF.

Skin and subcutaneous tissue disorders.

Acute febrile neutrophilic dermatosis (Sweet's syndrome); cutaneous vasculitis.

4.2 Dose and Method of Administration

Dosage and administration.

Lonquex treatment should be initiated and supervised by physicians experienced in oncology or haematology.
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.
The recommended dosage of Lonquex is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle.

Dosage.

One 6 mg dose of Lonquex (a single prefilled syringe of Lonquex) is recommended for each chemotherapy cycle, given approximately 24 hours after cytotoxic chemotherapy. The maximum amount of Lonquex that can be safely administered as a single dose has not been determined.

Preparation and administration of Lonquex.

Lonquex does not contain any preservative. In view of the possible risk of microbial contamination, Lonquex syringes are for single use in one patient only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Only clear, colorless solutions without particles should be used. Do not use this medicine if you notice any particulate matter or discoloration.
Avoid vigorous shaking. Excessive shaking may aggregate lipegfilgrastim, rendering it biologically inactive.
Allow the ready to use pre-filled syringe to reach a comfortable temperature (15°C - 25°C) before injecting.

Method of administration.

The solution is injected subcutaneously (SC). The injections should be given into the abdomen, upper arm or thigh. Lonquex should not be injected into an area that is tender, red, bruised, or hard, or that has scars or stretch marks.
Self administration of Lonquex should only be performed by patients who are well motivated, adequately trained and have access to expert advice. The first injection of Lonquex should be performed under direct medical supervision.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Special populations.

Elderly patients.

In clinical studies with a limited number of elderly patients, there was no relevant age related difference with regard to the efficacy or safety profiles of Lonquex. Therefore, no adjustment of the dose is necessary for elderly patients.
No alternative dosage regimes are currently recommended for patients affected by renal or hepatic impairment (see Section 5 Pharmacological Properties).

Paediatric population.

The safety and efficacy of Lonquex in children and adolescents aged less than 18 years have not yet been established. No data are available.

4.7 Effects on Ability to Drive and Use Machines

Lonquex has no or negligible influence on the ability to drive and use machines.

4.9 Overdose

There is no experience with overdose of lipegfilgrastim. In the case of overdose, WBC and platelet count should be performed regularly and spleen size should be carefully monitored (e.g. clinical examination, ultrasound).
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The product is formulated at a concentration of 10 mg/mL in a 10 mM sodium acetate buffer (pH 5.0), 50 mg/mL sorbitol (30.0 mg) and polysorbate 20 (0.02 mg). Other excipients used in the formulation are acetic acid (0.36 mg), 1 M sodium hydroxide (0.14 mg) and water for injection (q.s. to 0.6 mL). The concentration of 10 mg/mL is based on protein content only. The concentration is 20.9 mg/mL (i.e. 12.6 mg per prefilled syringe) if the PEG moiety and the carbohydrate linker are included.

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 in a refrigerator between 2-8°C. Do not freeze.
Keep the prefilled syringe in the outer carton, in order to protect from light.
Avoid shaking.
Lonquex may be removed from the refrigerator and stored below 25°C for a maximum single period of up to 3 days. Once removed from the refrigerator, the medicinal product must be used within this period or disposed of.

6.5 Nature and Contents of Container

Lonquex is supplied as a single use, preservative free, solution in a pre-filled syringe (type I glass) with a bromobutyl, latex free, plunger stopper and a fixed injection needle (stainless steel, 29G [0.34 mm] x 0.5 inch [12.7 mm]). It contains a solution volume of 0.6 mL with 6 mg of the active ingredient, lipegfilgrastim, for a 10 mg/mL solution. This is based on the protein content only.
Pack sizes of 1 pre-filled syringe with or without safety device (which prevents needle stick injury and re-use). For syringes without safety device, a plunger rod (polypropylene) is attached.
Each syringe is supplied in its own blister and carton.

6.6 Special Precautions for Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes