Ziextenzo

Evrópusambandið - enska - EMA (European Medicines Agency)

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Upplýsingar fylgiseðill PIL
Vara einkenni SPC
Opinber matsskýrsla PAR
Virkt innihaldsefni:
pegfilgrastim
Fáanlegur frá:
Sandoz GmbH
ATC númer:
L03AA13
INN (Alþjóðlegt nafn):
pegfilgrastim
Meðferðarhópur:
Immunostimulants,
Lækningarsvæði:
Neutropenia
Ábendingar:
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).,
Vörulýsing:
Revision: 2
Leyfisstaða:
Authorised
Leyfisnúmer:
EMEA/H/C/004802
Leyfisdagur:
2018-11-22
EMEA númer:
EMEA/H/C/004802

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B. PACKAGE LEAFLET

Package leaflet: Information for the user

Ziextenzo 6 mg solution for injection in pre-filled syringe

pegfilgrastim

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety

information. You can help by reporting any side effects you may get. See the end of section 4 for how to

report side effects.

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their symptoms of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Ziextenzo is and what it is used for

What you need to know before you use Ziextenzo

How to use Ziextenzo

Possible side effects

How to store Ziextenzo

Contents of the pack and other information

1.

What Ziextenzo is and what it is used for

Ziextenzo contains the active substance pegfilgrastim. Pegfilgrastim is a protein produced by

biotechnology in bacteria called

E. coli

. It belongs to a group of proteins called cytokines, and is very

similar to a natural protein (granulocyte-colony stimulating factor) produced by your own body.

Ziextenzo is used to reduce the duration of neutropenia (low white blood cell count) and the occurrence

of febrile neutropenia (low white blood cell count with a fever) which can be caused by the use of

cytotoxic chemotherapy (medicines that destroy rapidly growing 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.

Your doctor has given you Ziextenzo to encourage your bone marrow (part of the bone which makes

blood cells) to produce more white blood cells that help your body fight infection.

2.

What you need to know before you use Ziextenzo

Do not use Ziextenzo

if you are allergic to pegfilgrastim, filgrastim

,

or any of the other ingredients of this medicine

(listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Ziextenzo:

if you experience an allergic reaction including weakness, drop in blood pressure, difficulty

breathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the skin

that itch.

if you experience a cough, fever and difficulty breathing. This can be a sign of Acute Respiratory

Distress Syndrome (ARDS).

if you have any of the following or combination of the following side effects:

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 could be symptoms of condition called “Capillary Leak Syndrome” which causes blood to

leak from the small blood vessels into your body. See section 4.

if you get left upper abdominal pain or pain at the tip of your shoulder. This may be a sign of a

problem with your spleen (splenomegaly).

if you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary

oedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung

infiltration).

if you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) or

decreased blood platelet counts, which reduces the ability of your blood to clot

(thrombocytopenia). Your doctor may want to monitor you more closely.

if you have sickle cell anaemia. Your doctor may monitor your condition more closely.

if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face,

lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing these

could be signs of a severe allergic reaction.

Inflammation of the aorta (the large blood vessel which transports blood from the heart to the

body) has been reported rarely in cancer patients and healthy donors. The symptoms can include

fever, abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor

if you experience these symptoms.

Your doctor will check your blood and urine regularly as pegfilgrastim can harm the tiny filters inside

your kidneys (glomerulonephritis).

Severe skin reactions (Stevens-Johnson syndrome) have been reported with the use of Ziextenzo. Stop

using Ziextenzo and seek medical attention immediately if you notice any of the symptoms described in

section 4.

You should talk to your doctor about your risks of developing cancers of the blood. If you develop or

are likely to develop cancers of the blood, you should not use Ziextenzo, unless instructed by your

doctor.

Loss of response to pegfilgrastim

If you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, your

doctor will investigate the reasons why, including whether you have developed antibodies which

neutralise pegfilgrastim’s activity.

Other medicines and Ziextenzo

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. Pegfilgrastim has not been tested

in pregnant women. It is important to tell your doctor if you:

are pregnant;

think you may be pregnant; or

are planning to have a baby.

If you become pregnant during Ziextenzo treatment, please inform your doctor.

Unless your doctor directs you otherwise, you must stop breast-feeding if you use Ziextenzo.

Driving and using machines

Ziextenzo has no or negligible effect on the ability to drive or use machines.

Ziextenzo contains sorbitol (E420) and sodium

This medicine contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg / mL.

This medicine contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially

‘sodium-free’.

3.

How to use Ziextenzo

Ziextenzo is for use in adults aged 18 and over.

Always use Ziextenzo exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are unsure. The usual dose is one 6 mg subcutaneous injection (injection under your

skin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of

chemotherapy at the end of each chemotherapy cycle.

Injecting Ziextenzo yourself

Your doctor may decide that it would be more convenient for you to inject Ziextenzo yourself. Your

doctor or nurse will show you how to inject yourself. Do not try to inject yourself if you have not been

trained.

For further instructions on how to inject yourself with Ziextenzo, please read the section at the end of

this leaflet.

Do not shake Ziextenzo vigorously as this may affect its activity.

If you use more Ziextenzo than you should

If you use more Ziextenzo than you should contact your doctor, pharmacist or nurse.

If you forget to inject Ziextenzo

If you are injecting yourself and have forgotten a dose of Ziextenzo, you should contact your doctor to

discuss when you should inject the next dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Please tell your doctor immediately if you have any of the following or combination of the following

side effects:

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 an uncommon (may affect up to 1 in 100 people) condition called

“Capillary Leak Syndrome” which causes blood to leak from the small blood vessels into your body and

needs urgent medical attention.

Very common side effects

(may affect more than 1 in 10 people):

bone pain. Your doctor will tell you what you can take to ease the bone pain.

nausea and headaches.

Common side effects

(may affect up to 1 in 10 people):

pain at the site of injection.

general aches and pains in the joints and muscles.

some changes may occur in your blood, but these will be detected by routine blood tests. Your

white blood cell count may become high for a short period of time. Your platelet count may

become low which might result in bruising.

Uncommon side effects

(may affect up to 1 in 100 people):

allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin that

itch.

serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty

breathing, swelling of the face).

increased spleen size.

spleen rupture. Some cases of splenic rupture were fatal. It is important that you 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.

breathing problems. If you have a cough, fever and difficulty breathing please tell your doctor.

Sweet’s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face

and neck with fever) has occurred but other factors may play a role.

cutaneous vasculitis (inflammation of the blood vessels in the skin).

damage to the tiny filters inside your kidneys (glomerulonephritis).

redness at the site of injection.

coughing up blood (haemoptysis)

Rare side effects

(may affect up to 1 in 1,000 people):

inflammation of the aorta (the large blood vessel which transports blood from the heart to the

body), see section 2.

bleeding from the lung (pulmonary haemorrhage).

Stevens-Johnson syndrome, which can appear as reddish target-like or circular patches often with

central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can

be preceded by fever and flu-like symptoms. Stop using Ziextenzo if you develop these symptoms

and contact your doctor or seek medical attention immediately. See also section 2.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store Ziextenzo

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the syringe label after

EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2 °C – 8 °C).

You may take Ziextenzo out of the refrigerator and keep it at room temperature (not above 35 °C) for no

longer than 120 hours. Once a syringe has been removed from the refrigerator and has reached room

temperature (not above 35 °C) it must either be used within 120 hours or disposed of.

Do not freeze. Ziextenzo may be used if it is accidentally frozen for a single period of less than 24

hours.

Keep the container in the outer carton in order to protect from light.

Do not use this medicine if you notice it is cloudy or there are particles in it.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Ziextenzo contains

The active substance is pegfilgrastim. Each pre-filled syringe contains 6 mg of pegfilgrastim in

0.6 mL of solution.

The other ingredients are glacial acetic acid, sorbitol (E420), polysorbate 20, sodium hydroxide

and water for injections. See section 2 “Ziextenzo contains sorbitol (E420) and sodium”.

What Ziextenzo looks like and contents of the pack

Ziextenzo is a clear, colourless to slightly yellowish solution for injection in a pre-filled syringe

(6 mg/0.6 mL).

Each pack contains 1 glass pre-filled syringe with a rubber plunger stopper, a plunger rod, an attached

stainless steel needle and needle cap. The syringes are provided with an automatic needle guard.

Marketing Authorisation Holder

Sandoz GmbH

Biochemiestr. 10

6250 Kundl

Austria

Manufacturer

Sandoz GmbH

Biochemiestr. 10

6336 Langkampfen

Austria

This leaflet was last revised in {MM/YYYY}.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

Instructions for use of Ziextenzo pre-filled syringe

To help avoid possible infections and to ensure that you use the medicine correctly, it is important that

you follow these instructions.

Read ALL the way through these instructions before injecting. It is important not to try to inject yourself

until you have been trained by your doctor, nurse or pharmacist. The carton contains the pre-filled

syringe individually sealed in a plastic blister.

Your Ziextenzo pre-filled syringe with needle guard

After the medicine has been injected, the needle guard will be activated to cover the needle. The needle

guard is intended to protect healthcare professionals, caregivers and patients from accidental needle

sticks after the injection.

What you additionally need for

your injection:

Alcohol swab.

Cotton ball or gauze.

Sharps disposal container.

Important safety information

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

Do not open the carton until you are ready to use the pre-filled syringe.

Do not use the pre-filled syringe if the seal of the blister is broken, as it may not be safe for you to

use.

Never leave the pre-filled syringe unattended where others might tamper with it.

Do not shake the pre-filled syringe.

Be careful not to touch the needle guard wings before use. By touching them, the needle guard

may be activated too early.

Do not remove the needle cap until just before you give the injection.

The pre-filled syringe cannot be re-used. Dispose of the used pre-filled syringe immediately after

use in a sharps container.

Storage of the Ziextenzo pre-filled syringe

Store the blistered pre-filled syringe in its carton to protect it from light.

Store in the refrigerator between 2 °C and 8 °C.

Do not freeze

Prior to use‚ remove the pre-filled syringe from the refrigerator and allow Ziextenzo to reach

room temperature (up to a maximum of 35 °C) for approximately 15-30 minutes.

Do not use

the pre-filled syringe after the expiry date which is stated on the carton or syringe

label. If it has expired, return the entire pack to the pharmacy.

The injection site

The injection site is the place on the body where you are

going to use the pre-filled syringe.

The recommended site is the front of your thighs. You

may also use the lower abdomen, but

not

the area

5 centimetres around the navel (belly button).

Choose a different site each time you give yourself an

injection.

Do not inject into areas where the skin is tender,

bruised, red, scaly or hard. Avoid areas with scars or

stretch marks.

If a caregiver is giving you the injection, the outer upper

arms may also be used.

Preparing the Ziextenzo pre-filled syringe ready for use

Take the carton containing the blistered pre-filled syringe out of the refrigerator and leave it

unopened

for approximately 15-30 minutes so that it reaches room temperature.

When you are ready to use the pre-filled syringe, open the blister and wash your hands thoroughly

with soap and water.

Clean the injection site with an alcohol swab.

Remove the pre-filled syringe from the blister.

Check to ensure the plastic transparent needle

guard is situated over the barrel of the glass syringe. If the transparent needle guard is covering

the needle cap (as shown below) the syringe has been activated, DO NOT use this syringe and

take a new syringe. The figure below shows a ready to use syringe.

Inspect the pre-filled syringe. The liquid should be clear. Its colour may vary from colourless to

slightly yellowish. You may see a small air bubble in the liquid. This is normal.

Do not use

pre-filled syringe if any other particulates and/or discolouration are observed.

Do not use

if the syringe is broken or activated. Return the Ziextenzo pre-filled syringe and the

package to your pharmacy.

Device ACTIVATED – DO NOT USE

In this configuration the needle guard is

ACTIVATED – DO NOT USE the pre-filled syringe

Device READY TO BE USED

In this configuration the needle guard is NOT

ACTIVATED and the pre-filled syringe is ready for

use

How to use the Ziextenzo pre-filled syringe

1

Carefully pull the needle cap straight off. You may

see a drop of liquid at the end of the needle. This

is normal.

2

Gently pinch the skin at the injection site and insert

the needle as shown. Push the needle all the way in

to ensure that the medicine can be fully

administered.

3

Holding the pre-filled syringe as shown,

slowly

depress

the plunger

as

far as it will go

so that the plunger head

is completely between the needle guard wings.

Keep the plunger pressed fully down while you hold the

syringe in place for 5 seconds.

4

Keep the plunger fully

depressed

while you carefully

pull the needle straight out from the injection site and

let it go off your skin.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new

safety information. Healthcare professionals are asked to report any suspected adverse reactions. See

section 4.8 for how to report adverse reactions.

1.

NAME OF THE MEDICINAL PRODUCT

Ziextenzo 6 mg solution for injection in pre-filled syringe

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 mL solution for injection. The

concentration is 10 mg/mL based on protein only**.

*Produced in

Escherichia coli

cells by recombinant DNA technology followed by conjugation with

polyethylene glycol (PEG).

** The concentration is 20 mg/mL if the PEG moiety is included.

The potency of this product should not be compared to the potency of another pegylated or

non-pegylated protein of the same therapeutic class. For more information, see section 5.1

Excipients with known effect

Each pre-filled syringe contains 30 mg sorbitol (E420).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection (injection)

Clear, colourless to slightly yellowish solution for injection.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

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).

4.2

Posology and method of administration

Ziextenzo therapy should be initiated and supervised by physicians experienced in oncology and/or

haematology.

Posology

One 6 mg dose (a single pre-filled syringe) of Ziextenzo is recommended for each chemotherapy cycle,

given at least 24 hours after cytotoxic chemotherapy.

Special populations

Paediatric population

The safety and efficacy of pegfilgrastim in children has not yet been established. Currently available

data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Patients with renal impairment

No dose change is recommended in patients with renal impairment, including those with end stage renal

disease.

Method of administration

Ziextenzo is for subcutaneous use. The injections should be given into the thigh, abdomen or upper arm.

For instructions on handling of the medicinal product before administration, see section 6.6.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

Traceability

In order to improve the traceability of granulocyte-colony stimulating factors (G-CSFs), the trade name

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

General warnings and precautions

Limited clinical data suggest a comparable effect on time to recovery of severe neutropenia for

pegfilgrastim to filgrastim in patients with

de novo

acute myeloid leukaemia (AML) (see section 5.1).

However, the long-term effects of pegfilgrastim have not been established in AML; therefore, it should

be used with caution in this patient population.

Granulocyte-colony stimulating factor can promote growth of myeloid cells

in vitro

and similar effects

may be seen on some non-myeloid cells

in vitro

The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic

syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should

not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast

transformation of chronic myeloid leukaemia from AML.

The safety and efficacy of pegfilgrastim administration in

de novo

AML patients aged < 55 years with

cytogenetics t(15;17) have not been established.

The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high dose

chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic

chemotherapy beyond established dosage regimens.

Pulmonary adverse events

Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF

administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher

risk (see section 4.8).

The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs

of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count

may be preliminary signs of Acute Respiratory Distress Syndrome (ARDS). In such circumstances

pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment

given (see section 4.8).

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally,

events of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and pegfilgrastim.

Urinalysis monitoring is recommended.

Capillary leak syndrome

Capillary leak syndrome has been reported after granulocyte-colony stimulating factor administration

and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who

develop symptoms of capillary leak syndrome should be closely monitored and receive standard

symptomatic treatment, which may include a need for intensive care (see section 4.8).

Splenomegaly and splenic rupture

Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases,

have been reported following administration of pegfilgrastim (see section 4.8). Therefore, spleen size

should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture

should be considered in patients reporting left upper abdominal pain or shoulder tip pain.

Thrombocytopenia and anaemia

Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose

myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of

platelet count and haematocrit is recommended. Special care should be taken when administering single

or combination chemotherapeutic agents which are known to cause severe thrombocytopenia.

Sickle cell anaemia

Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or

sickle cell disease (see section 4.8). Therefore, physicians should use caution when prescribing

pegfilgrastim in patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical

parameters and laboratory status and be attentive to the possible association of this medicine with

splenic enlargement and vaso-occlusive crisis.

Leukocytosis

White blood cell (WBC) counts of 100 x 10

/L or greater have been observed in less than 1% of patients

receiving pegfilgrastim. No adverse events directly attributable to this degree of leukocytosis have been

reported. Such elevation in white blood cells is transient, typically seen 24 to 48 hours after

administration and is consistent with the pharmacodynamic effects of this medicine. Consistent with the

clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals

during therapy. If leukocyte counts exceed 50 x 10

/L after the expected nadir, this medicine should be

discontinued immediately.

Hypersensitivity

Hypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment has been

reported in patients treated with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with

clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of

hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy

should be administered, with close patient follow-up over several days.

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.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of

antibodies against pegfilgrastim are generally low. Binding antibodies do occur as expected with all

biologics; however, they have not been associated with neutralising activity at present.

Aortitis

Aortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The

symptoms experienced included fever, abdominal pain, malaise, back pain and inflammatory markers

(e.g. C-reactive protein and white blood cell count) were raised. In most cases aortitis was diagnosed by

CT scan and generally resolved after withdrawal of G-CSF. See also section 4.8.

Other warnings

The safety and efficacy of pegfilgrastim for the mobilisation of blood progenitor cells in patients or

healthy donors have not been adequately evaluated.

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.

This medicinal product contains 30 mg sorbitol in each pre-filled syringe which is equivalent to

50 mg / mL. The additive effect of concomitantly administered products containing sorbitol (or fructose)

and dietary intake of sorbitol (or fructose) should be taken into account.

This medicinal product contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say

essentially ‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Due to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚

pegfilgrastim should be administered at least 24 hours after administration of cytotoxic chemotherapy. In

clinical trials, pegfilgrastim has been safely administered 14 days before chemotherapy. Concomitant

use of pegfilgrastim with any chemotherapy agent has not been evaluated in patients. In animal models

concomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or other antimetabolites has been

shown to potentiate myelosuppression.

Possible interactions with other haematopoietic growth factors and cytokines have not been specifically

investigated in clinical trials.

The potential for 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.

The safety and efficacy of pegfilgrastim have not been evaluated in patients receiving chemotherapy

associated with delayed myelosuppression e.g. nitrosoureas.

Specific interaction or metabolism studies have not been performed, however, clinical trials have not

indicated an interaction of pegfilgrastim with any other medicinal products.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in

animals have shown reproductive toxicity (see section 5.3). Pegfilgrastim is not recommended during

pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

There is insufficient information on the excretion of pegfilgrastim/metabolites in human milk, a risk to

the newborns/infants cannot be excluded. A decision must be made whether to discontinue

breast-feeding or to discontinue/abstain from pegfilgrastim therapy taking into account the benefit of

breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative

weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body

surface area) (see section 5.3).

4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and

musculoskeletal pain (common [≥ 1/100 to < 1/10]). Bone pain was generally of mild to moderate

severity, transient and could be controlled in most patients with standard analgesics.

Hypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythaema,

flushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon

[≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients receiving

pegfilgrastim (uncommon) (see section 4.4).

Capillary Leak Syndrome, which can be life-threatening if treatment is delayed, has been reported as

uncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following administration

of granulocyte colony-stimulating factors; see section 4.4 and section “Description of selected adverse

reactions” below.

Splenomegaly, generally asymptomatic, is uncommon.

Splenic rupture including some fatal cases is uncommonly reported following administration of

pegfilgrastim (see section 4.4).

Uncommon pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema,

pulmonary infiltrates and pulmonary fibrosis have been reported. Uncommonly, cases have resulted in

respiratory failure or ARDS, which may be fatal (see section 4.4).

Isolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell

disease (uncommon in sickle cell patients) (see section 4.4).

Tabulated summary of adverse reactions

The data in the table below describe adverse reactions reported from clinical trials and spontaneous

reporting. Within each frequency grouping, undesirable effects are presented in order of decreasing

seriousness.

MedDRA

system organ

class

Adverse reactions

Very

common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to

< 1/100)

Rare

(≥ 1/10,000

to

< 1/1,000)

Very rare

(< 1/10,000)

Blood and

lymphatic

system

disorders

Thrombocytopenia

Leukocytosis

Sickle cell crisis

Splenomegaly

Splenic rupture

Immune system

disorders

Hypersensitivity

reactions;

Anaphylaxis

Metabolism

and nutrition

disorders

Elevations in uric

acid

Nervous system

disorders

Headache

Vascular

disorders

Capillary leak

syndrome

Aortitis

Respiratory,

thoracic and

mediastinal

disorders

Acute respiratory

distress syndrome

Pulmonary adverse

reactions

(interstitial

pneumonia,

pulmonary oedema,

pulmonary

infiltrates and

pulmonary fibrosis)

Haemoptysis

Pulmonary

haemorrhage

Gastrointestinal

disorders

Nausea

Skin and

subcutaneous

tissue disorders

Sweet’s syndrome

(acute febrile

dermatosis)

Cutaneous

vasculitis

Stevens-

Johnson

syndrome

Musculoskeletal

and connective

tissue disorders

Bone pain

Musculoskeletal

pain (myalgia,

arthralgia, pain in

extremity, back

pain, musculo-

skeletal pain, neck

pain)

Renal and

urinary

disorders

Glomerulonephritis

General

disorders and

Injection site pain

Non-cardiac chest

Injection site

reactions

MedDRA

system organ

class

Adverse reactions

Very

common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to

< 1/100)

Rare

(≥ 1/10,000

to

< 1/1,000)

Very rare

(< 1/10,000)

administrative

site conditions

pain

Investigations

Elevations in lactate

dehydrogenase and

alkaline

phosphatase

Transient elevations

in LFT's for ALT or

See section “Description of selected adverse reactions” below.

This adverse reaction was identified through post-marketing surveillance but not observed in

randomised, controlled clinical trials in adults. The frequency category was estimated from a statistical

calculation based upon 1,576 patients receiving pegfilgrastim in nine randomised clinical trials.

Description of selected adverse reactions

Uncommon cases of Sweet’s syndrome have been reported, although in some cases underlying

haematological malignancies may play a role.

Uncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. The

mechanism of vasculitis in patients receiving pegfilgrastim is unknown.

Injection site reactions, including injection site erythaema (uncommon) as well as injection site pain

(common) have occurred on initial or subsequent treatment with pegfilgrastim.

Common cases of leukocytosis (White Blood Count [WBC] > 100 x 10

/L) have been reported (see

section 4.4).

Reversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated clinical

effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, with no

associated clinical effects, were uncommon in patients receiving pegfilgrastim following cytotoxic

chemotherapy.

Nausea and headaches were very commonly observed in patients receiving chemotherapy.

Uncommon elevations in liver function tests (LFTs) for alanine aminotransferase (ALT) or aspartate

aminotransferase (AST), have been observed in patients after receiving pegfilgrastim following

cytotoxic chemotherapy. These elevations are transient and return to baseline.

Common cases of thrombocytopenia have been reported.

Cases of capillary leak syndrome have been reported in the post-marketing setting with granulocyte

colony-stimulating factor use. These have generally occurred in patients with advanced malignant

diseases, sepsis, taking multiple chemotherapy medicinal products or undergoing apheresis (see

section 4.4).

Paediatric population

The experience in children is limited. A higher frequency of serious adverse reactions in younger

children aged 0-5 years (92%) has been observed compared to older children aged 6-11 and 12-21 years

respectively (80% and 67%) and adults. The most common adverse reaction reported was bone pain (see

section 5.1 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

4.9

Overdose

Single doses of 300 mcg/kg have been administered subcutaneously to a limited number of healthy

volunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse

events were similar to those in subjects receiving lower doses of pegfilgrastim.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code: L03AA13

Ziextenzo is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu

Human granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the production

and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of recombinant

human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule. Pegfilgrastim

is a sustained duration form of filgrastim due to decreased renal clearance.

Pegfilgrastim and filgrastim have been shown to have identical modes of action, causing a marked

increase in peripheral blood neutrophil counts within 24 hours, 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. 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

similar

effects may be seen on some non-myeloid cells

in vitro

In two randomised, double-blind, pivotal studies in patients with high-risk stage II-IV breast cancer

undergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of

pegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence of

febrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of

11 daily administrations). In the absence of growth factor support, this regimen has been reported to

result in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40% incidence of febrile

neutropenia. In one study (n = 157), which used a 6 mg fixed dose of pegfilgrastim the mean duration of

grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the filgrastim

group (difference 0.23 days, 95% CI -0.15, 0.63). Over the entire study, the rate of febrile neutropenia

was 13% of pegfilgrastim-treated patients compared with 20% of filgrastim-treated patients (difference

7%, 95% CI of -19%, 5%). In a second study (n = 310), which used a weight-adjusted dose (100 µg/kg),

the mean duration of grade 4 neutropenia for the pegfilgrastim group was 1.7 days, compared with

1.8 days in the filgrastim group (difference 0.03 days, 95% CI-0.36, 0.30). The overall rate of febrile

neutropenia was 9% of patients treated with pegfilgrastim and 18% of patients treated with filgrastim

(difference 9%, 95% CI of -16.8%, -1.1%).

In a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on

the incidence of febrile neutropenia was evaluated following administration of a chemotherapy regimen

associated with a febrile neutropenia rate of 10-20% (docetaxel 100 mg/m

every 3 weeks for 4 cycles).

Nine hundred and twenty eight patients were randomised to receive either a single dose of pegfilgrastim

or placebo approximately 24 hours (day 2) after chemotherapy in each cycle. The incidence of febrile

neutropenia was lower for patients randomised to receive pegfilgrastim compared with placebo (1%

versus 17%, p < 0.001). The incidence of hospitalisations and IV anti-infective use associated with a

clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group compared with placebo

(1% versus 14%, p < 0.001; and 2% versus 10%, p < 0.001).

A small (n = 83), Phase II, randomised, double-blind study 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 (see section 4.4).

In a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients receiving

100 mcg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide

(VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 x 10

) was

observed in younger children aged 0-5 years (8.9 days) compared to older children aged 6-11 years and

12-21 years (6 days and 3.7 days, respectively) and adults. Additionally a higher incidence of febrile

neutropenia was observed in younger children aged 0-5 years (75%) compared to older children aged

6-11 years and 12-21 years (70% and 33%, respectively) and adults (see sections 4.8 and 5.2).

5.2

Pharmacokinetic properties

After a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim occurs

at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained during the

period of neutropenia after myelosuppressive chemotherapy. The elimination of pegfilgrastim is

non-linear with respect to dose; serum clearance of pegfilgrastim decreases with increasing dose.

Pegfilgrastim 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 pegfilgrastim declines rapidly at the onset of neutrophil recovery (see Figure 1).

Figure 1. Profile of median pegfilgrastim serum concentration and absolute neutrophil count

(ANC) in chemotherapy treated patients after a single 6 mg injection

Due to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not

expected to be affected by renal or hepatic impairment. In an open-label, single dose study (n = 31)

various stages of renal impairment, including end-stage renal disease, had no impact on the

pharmacokinetics of pegfilgrastim.

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© European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged.

EMA/653854/2018

EMEA/H/C/004802

Ziextenzo (pegfilgrastim)

An overview of Ziextenzo and why it is authorised in the EU

What is Ziextenzo and what is it used for?

Ziextenzo is a medicine used in cancer patients to help with neutropenia (low levels of neutrophils, a

type of white blood cell), which is a common side effect of cancer treatment and can leave patients

vulnerable to infections.

It is given specifically to reduce the duration of neutropenia and prevent febrile neutropenia (when

neutropenia is accompanied by fever).

Ziextenzo is not intended for use in patients with the blood cancer chronic myeloid leukaemia or with

myelodysplastic syndromes (conditions in which large numbers of abnormal blood cells are produced,

which can develop into leukaemia).

Ziextenzo is a ‘biosimilar medicine’. This means that Ziextenzo is highly similar to another biological

medicine (the ‘reference medicine’) that is already authorised in the EU. The reference medicine for

Ziextenzo is Neulasta. For more information on biosimilar medicines, see here

How is Ziextenzo used?

Ziextenzo can only be obtained with a prescription and treatment should be started and supervised by

a doctor who has experience in the treatment of cancer or blood disorders. It is available as a prefilled

syringe containing a solution for injection under the skin. Ziextenzo is given as a single dose of 6 mg

injected under the skin at least 24 hours after the end of each cycle of chemotherapy (treatment with

cancer medicines). Patients can inject themselves if they have been trained appropriately.

For more information about using Ziextenzo, see the package leaflet or contact your doctor or

pharmacist.

How does Ziextenzo work?

The active substance in Ziextenzo, pegfilgrastim, is a form of filgrastim, which is very similar to a

human protein called granulocyte-colony-stimulating factor (G-CSF). Filgrastim works by encouraging

Ziextenzo (pegfilgrastim)

EMA/653854/2018

Page 2/3

the bone marrow to produce more white blood cells, increasing white blood cell counts and so treating

neutropenia.

Filgrastim has been available in other medicines in the European Union (EU) for a number of years. In

Ziextenzo, filgrastim has been ‘pegylated’ (attached to a chemical called polyethylene glycol). This

slows down the removal of filgrastim from the body, allowing the medicine to be given less often.

What benefits of Ziextenzo have been shown in studies?

Laboratory studies comparing Ziextenzo with Neulasta have shown that the active substance in

Ziextenzo is highly similar to that in Neulasta in terms of structure, purity and biological activity.

Studies have also shown that giving Ziextenzo produces similar levels of the active substance in the

body to giving Neulasta.

In addition, two studies involving 624 patients who had chemotherapy before or after surgery for

breast cancer showed that Ziextenzo was as effective as Neulasta in reducing the duration of

neutropenia. Neutropenia lasted 1 day on average with both medicines.

Because Ziextenzo is a biosimilar medicine, the studies on effectiveness and safety of pegfilgrastim

carried out with Neulasta do not all need to be repeated for Ziextenzo.

What are the risks associated with Ziextenzo?

The safety of Ziextenzo has been evaluated, and on the basis of all the studies carried out the side

effects of the medicine are considered to be comparable to those of the reference medicine Neulasta.

The most common side effect with Ziextenzo (which may affect more than 1 in 10 people) is pain in

the bones. Pain in muscles is also common. For the full list of side effects and restrictions with

Ziextenzo, see the package leaflet.

Why is Ziextenzo authorised in the EU?

The European Medicines Agency decided that, in accordance with EU requirements for biosimilar

medicines, Ziextenzo has a highly similar structure, purity and biological activity to Neulasta and is

distributed in the body in the same way. In addition, studies in breast cancer patients undergoing

chemotherapy have shown that the effectiveness of Ziextenzo is equivalent to that of Neulasta in

reducing the duration of neutropenia.

All these data were considered sufficient to conclude that Ziextenzo will behave in the same way as

Neulasta in terms of effectiveness and safety in its authorised uses. Therefore, the Agency’s view was

that, as for Neulasta, the benefit of Ziextenzo outweighs the identified risk and it can be authorised for

use in the EU.

What measures are being taken to ensure the safe and effective use of

Ziextenzo?

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Ziextenzo have been included in the summary of product characteristics and the

package leaflet.

As for all medicines, data on the use of Ziextenzo are continuously monitored. Side effects reported

with Ziextenzo are carefully evaluated and any necessary action taken to protect patients.

Ziextenzo (pegfilgrastim)

EMA/653854/2018

Page 3/3

Other information about Ziextenzo

Ziextenzo received a marketing authorisation valid throughout the EU on 22 November 2018.

Further information on Ziextenzo can be found on the Agency’s website:

https://www.ema.europa.eu/en/medicines/human/EPAR/ziextenzo

This overview was last updated in 11-2018.

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