NEUPOGEN 48 MU Pre-filled syringe

1

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only.

Neupogen 30 MU Pre-filled syringe

Neupogen 48 MU Pre-filled syringe

Neupogen 30 MU Vials

for intravenous/subcutaneous administration

Composition:

Each Neupogen 30 MU syringe contains 30 million units (300 micrograms (mcg)) of filgrastim in 0.5 ml

(0.6 mg/ml).

Each Neupogen 48 MU syringe contains 48 million units (480 micrograms (mcg)) of filgrastim in 0.5 ml

(0.96 mg/ml).

Each Neupogen 30 MU vial contains 30 million units (300 micrograms (mcg)) of filgrastim in 1 ml (0.3 mg/ml).

For inactive ingredients and allergens in the medicine – see section 6 “Further information’’

Read all of this leaflet carefully and until the end before using this medicine. This leaflet contains concise

information about the medicine. If you have further questions, contact your doctor, nurse or pharmacist.

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

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

seems to you that their medical condition is similar.

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.

Important information for your attention

You can inject Neupogen 30 MU pre-filled syringe, Neupogen 48 MU pre-filled syringe yourself in your

home after receiving instructions from your healthcare professional. Please carefully read the instructions

for self-injection of Neupogen pre-filled syringe that appear at the end of this leaflet.

Injecting Neupogen 30 MU vials is done by a healthcare professional staff only.

Strict adherence to the doctor’s instructions (dosage, injection times and duration of treatment) increases

the chance of treatment success. In any case, do not discontinue the treatment without consulting the

attending doctor. Please read sections 2 and 4 for expanded safety information.

During treatment regular blood tests should be performed.

Keep Neupogen in the refrigerator (see section 5).

Neupogen is intended for single use!

1.

WHAT IS THE MEDICINE INTENDED FOR?

Neupogen is a white blood cell growth factor (granulocyte-colony stimulating factor) and belongs to a group of

medicines called cytokines. Growth factors are proteins that are produced naturally in the body but they can also

be made using biotechnology for use as a medicine.

Neupogen works by encouraging the bone marrow to produce more white blood cells.

A reduction in the number of white blood cells (neutropenia) can occur for several reasons and makes your body

less able to fight infection.

Neupogen stimulates the bone marrow to produce new white cells quickly.

Neupogen can be used:

to increase the number of white blood cells after treatment with chemotherapy to help prevent infections.

to increase the number of white blood cells after a bone marrow transplant to help prevent infections.

before high-dose chemotherapy to make the bone marrow produce more stem cells, which can be

collected and given back to you after your treatment. These can be taken from you or from a donor. The

stem cells will then go back into the bone marrow and produce blood cells.

to increase the number of white blood cells if you suffer from severe chronic neutropenia (SCN) to help

prevent infections.

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Therapeutic group: Cytokines

2.

BEFORE USING THIS MEDICINE

X Do not use Neupogen if:

you are sensitive (allergic) to filgrastim or any of the other ingredients of this medicine (listed in section 6

– “Further information”).

! Special warnings regarding the usage of the medicine

Talk to your doctor, pharmacist or nurse before using Neupogen.

Please tell your doctor before starting treatment if you have:

sickle cell anemia, as Neupogen may cause sickle cell crisis.

an allergy to natural rubber (latex). The needle cover on the syringe may be made from a type of natural

rubber and may cause allergic reactions.

osteoporosis (bone disease).

Please tell your doctor immediately during treatment with Neupogen 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 as these could be signs of a

severe allergic reaction (hypersensitivity).

experience puffiness in your face or ankles, blood in your urine or brown-colored urine or you notice you

urinate less than usual (glomerulonephritis).

get left upper belly (abdominal) pain, pain below the left rib cage or at the tip of your left shoulder (these

may be symptoms of an enlarged spleen [splenomegaly], or possibly rupture of the spleen).

notice unusual bleeding or bruising (these may be symptoms of a decrease in blood platelets

[thrombocytopenia], with a reduced ability of your blood to clot).

Inflammation of 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 those

symptoms.

Children and adolescents

Neupogen

is used to treat children who are receiving chemotherapy or who suffer from severe low white blood

cell count (neutropenia). The dosing in children receiving chemotherapy is the same as for adults.

Tests and follow-up

If you suffer from severe chronic neutropenia, it is recommended that during treatment with Neupogen, periodic

tests be performed to check the bone marrow status.

Loss of response to filgrastim

If you experience a loss of response or failure to maintain a response with filgrastim treatment, your doctor will

investigate the reasons why including whether you have developed antibodies which neutralize filgrastim’s

activity.

Your doctor may want to monitor you closely, see section 4 of the patient package leaflet.

If you are a patient with severe chronic neutropenia, you may be at risk of developing cancer of the blood

(leukemia, myelodysplastic syndrome [MDS]). You should talk to your doctor about your risks of developing

cancers of the blood and what testing should be done. If you develop or are likely to develop cancers of the

blood, you should not use Neupogen, unless instructed by your doctor.

If you are a stem cell donor, you must be aged between 16 and 60 years.

Take special care with other products that stimulate white blood cells

Neupogen is one of a group of products that stimulate the production of white blood cells. Your healthcare

professional should always record the exact product you are using.

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Other medicines and Neupogen

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

including non-prescription medicines and nutritional supplements.

Do not start treatment with Neupogen from 24 hours before and until 24 hours after receiving chemotherapy.

Pregnancy and breast-feeding

Neupogen has not been tested in pregnant or breast-feeding women.

Neupogen is not recommended during pregnancy.

If you are pregnant, breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor

for advice before taking this medicine.

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

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

Driving and using machines

Neupogen may have a minor influence on your ability to drive and use machines. This medicine may cause

dizziness. It is advisable to wait and see how you feel after taking Neupogen and before driving or operating

machinery.

Important information about some of the ingredients of this medicine

Neupogen contains sodium

Neupogen contains less than 1 mmol (23 mg) sodium per 0.3/ 0.6/ 0.96 mg/ml, that is to say essentially 'sodium

free'.

Neupogen contains sorbitol

This medicine contains 50 mg sorbitol in each ml.

Sorbitol is a source of fructose. If you (or your child) have hereditary fructose intolerance (HFI), a rare genetic

disorder, you (or your child) must not receive this medicine. Patients with HFI cannot break down fructose,

which may cause serious side effects.

You must tell your doctor before receiving this medicine if you (or your child) have HFI or if your child can no

longer take sweet foods or drinks because they feel sick, vomit or get unpleasant effects such as bloating,

stomach cramps or diarrhea.

3.

HOW SHOULD YOU USE THE MEDICINE?

Always use this medicine exactly as your doctor has told you. Check with your doctor, nurse or pharmacist if

you are not sure regarding the dosage and how to use the medicine.

The dosage and treatment regimen will be determined by the doctor only.

How is

Neupogen

given and how much should I take?

Neupogen

is usually given as a daily injection into the tissue just under the skin (known as a subcutaneous

injection). It can also be given as a daily slow injection into the vein (known as an intravenous infusion). The

usual dose varies depending on your illness and weight.

Patients having a bone marrow transplant after chemotherapy:

You will normally receive your first dose of

Neupogen

at least 24 hours after your chemotherapy and at least

24 hours after receiving your bone marrow transplant.

You, or people caring for you, can be taught how to give subcutaneous injections so that you can continue your

treatment at home. However, you should not attempt this unless you have been properly trained first by your

healthcare provider.

Do not exceed the recommended dose

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How long will I have to take Neupogen?

You will need to take Neupogen until your white blood cell count is normal. Regular blood tests will be taken to

monitor the number of white blood cells in your body. Your doctor will tell you how long you will need to take

Neupogen.

If you accidentally use a higher dosage

Do not increase the dose your doctor has given you. If you think you have injected more than you should,

contact your doctor as soon as possible.

If you took an overdose or if a child accidentally swallowed the medicine, refer to the doctor or proceed to a

hospital emergency room immediately and bring the package of the medicine with you.

If you forget to use

Neupogen

If you have missed an injection, or injected too little, contact your doctor as soon as possible.

Do not take a double dose to make up for any missed doses.

Adhere to the treatment recommended by the doctor.

Even if there is an improvement in your health, do not discontinue treatment with the medicine without

consulting the doctor or pharmacist.

Do not take medicines in the dark! Check the label and the dose each time you take medicine. Wear glasses if

you need them.

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

4.

SIDE EFFECTS

As with any medicine, use of Neupogen may cause side effects in some users. Do not be alarmed when reading

the list of side effects. You may not suffer from any of them.

Refer to the doctor immediately if you notice any of the following effects:

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

swelling of the face (anaphylaxis), skin rash, itchy rash (urticaria), swelling of the face, lips, mouth,

tongue or throat (angioedema) and shortness of breath (dyspnea).

if you experience a cough, fever and difficulty breathing (dyspnea), as this can be a sign of Acute

Respiratory Distress Syndrome (ARDS).

if you experience kidney injury (glomerulonephritis). Kidney injury has been seen in patients who

received Neupogen. Call your doctor right away if you experience puffiness in your face or ankles, blood

in your urine or brown-colored urine or you notice you urinate less than usual.

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 a condition called “Capillary Leak Syndrome”, which causes blood to leak

from the small blood vessels into your body and needs urgent medical attention.

if you have a combination of any of the following symptoms:

fever, or shivering, or feeling very cold, high heart rate, confusion or disorientation, shortness of

breath, extreme pain or discomfort and clammy or sweaty skin.

These could be symptoms of a condition called “sepsis” (also called "blood poisoning"), a severe

infection with whole-body inflammatory response which can be life-threatening and needs urgent medical

attention.

if you get left upper belly (abdominal) pain, pain below the left rib cage or pain at the tip of your shoulder

as there may be a problem with your spleen (enlargement of the spleen [splenomegaly] or rupture of the

spleen).

if you are being treated for severe chronic neutropenia and you have blood in your urine (hematuria).

Your doctor may regularly test your urine if you experience this side effect or if protein is found in your

urine (proteinuria).

A very common side effect of

Neupogen

use is pain in your muscles or bones (musculoskeletal pain), which can

be helped by taking standard pain relief medicines (analgesics). In patients undergoing a stem cell or bone

marrow transplant, Graft versus host disease (GvHD) may occur - this is a reaction of the donor cells against the

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patient receiving the transplant. Signs and symptoms include rash on the palms of your hands or soles of your

feet and ulcer and sores in your mouth, gut, liver, skin or your eyes, lungs, vagina and joints.

In normal stem cell donors an increase in white blood cells (leukocytosis) and a decrease of platelets may be

seen, this reduces the ability of your blood to clot (thrombocytopenia), these will be monitored by your doctor.

Very common side effects (occur in more than 1 in 10 treated patients):

decrease of platelets which reduces the ability of blood to clot (thrombocytopenia)

low red blood cell count (anemia)

headache

diarrhea

vomiting

nausea

unusual hair loss or thinning (alopecia)

tiredness (fatigue)

soreness and swelling of the digestive tract lining which runs from the mouth to the anus (mucosal

inflammation)

fever (pyrexia)

Common side effects (occur in 1 – 10 out of 100 treated patients):

inflammation of the lung (bronchitis)

upper respiratory tract infection

urinary tract infection

decreased appetite

trouble sleeping (insomnia)

dizziness

decreased feeling of sensitivity, especially in the skin (hypoesthesia)

tingling or numbness of the hands or feet (paresthesia)

low blood pressure (hypotension)

high blood pressure (hypertension)

cough

coughing up blood (hemoptysis)

pain in your mouth and throat (oropharyngeal pain)

nose bleeds (epistaxis)

constipation

oral pain

enlargement of the liver (hepatomegaly)

rash

redness of the skin (erythema)

muscle spasm

pain when passing urine (dysuria)

chest pain

pain

generalized weakness (asthenia)

generally feeling unwell (malaise)

swelling in the hands and feet (edema peripheral)

increase of certain enzymes in the blood

changes in blood chemistry

transfusion reaction

Uncommon side effects (occur in 1 – 10 out of 1000 treated patients):

increase in white blood cells (leukocytosis)

allergic reaction (hypersensitivity)

rejection of transplanted bone marrow (graft versus host disease = GvHD)

high uric acid levels in the blood, which may cause gout (hyperuricemia) (blood uric acid increased)

liver damage caused by blocking of the small veins within the liver (veno-occlusive disease)

lungs do not function as they should, causing breathlessness (respiratory failure)

swelling and/or fluid in the lungs (pulmonary edema)

inflammation of the lungs (interstitial lung disease)

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abnormal x-rays of the lungs (lung infiltration)

bleeding from the lung (pulmonary hemorrhage)

lack of absorption of oxygen in the lung (hypoxia)

bumpy skin rash (rash maculo-papular)

disease which causes bones to become less dense, making them weaker, more brittle and likely to break

(osteoporosis)

injection site reaction

Rare side effects (occur in 1 – 10 out of 10,000 treated patients):

severe pain in the bones, chest, gut or joints (sickle cell anemia with crisis)

sudden life-threatening allergic reaction (anaphylactic reaction)

pain and swelling of the joints, similar to gout (pseudogout)

a change in how your body regulates fluids within your body and may result in puffiness (fluid volume

disturbances)

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

plum-colored, raised, painful sores on the limbs and sometimes the face and neck with a fever (Sweet's

syndrome)

worsening of rheumatoid arthritis

unusual change in the urine

bone density decreased

Inflammation of aorta (the large blood vessel which transports blood from the heart to the body), see

section 2

If you get any side effects, if one of the side effects is worsening, if you suffer from a side effect not listed in

the leaflet, you should consult with a doctor.

Reporting of side effects:

Side effects can be reported to the Ministry of Health by clicking on the link “Report Side

Effects of Drug Treatment” found on the Ministry of Health homepage www.health.gov.il that directs you to the

online form for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

5.

HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and all other medicines, must be stored in a safe place out of the reach

and sight of children and/or infants, to avoid poisoning. Do not induce vomiting unless explicitly

instructed to do so by a doctor.

Store in a refrigerator (2°C-8°C). Do not freeze. Keep the container in the outer carton in order to protect

from light.

Do not use this medicine after the expiry date (Exp. Date) which is stated on the syringe or vial and

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

Do not use this medicine if you notice discoloration, cloudiness or particles, it should be a clear, colorless

liquid.

Neupogen is intended for single use! If you have been prescribed a lower dose than the amount in

the syringe or vial, destroy the remainder after the injection!

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 protect the environment.

6.

FURTHER INFORMATION

In addition to the active ingredient, this medicine also contains:

Sorbitol, Glacial acetic acid, Polysorbate 80, Sodium hydroxide 1N ad pH 4, water for injection.

The medicine contains less than 1 mmol (23 mg) of sodium in 0.3/0.6/0.96 mg/ml of solution.

The medicine contains approx. 50 mg of sorbitol per 1 ml of solution.

What does the medicine look like and what are the contents of the package?

Neupogen

is a clear, colorless solution intended for subcutaneous injection or for intravenous infusion.

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Neupogen

is available in vials or in a pre-filled syringe with a separate needle.

Neupogen

30 MU Vials – 30 MU/1 ml is marketed in a package containing five vials.

Neupogen

30 MU pre-filled syringe - 30 MU/0.5 ml is marketed in a package containing 1 or 5 syringes*.

Neupogen

48 MU pre-filled syringe - 48 MU/0.5 ml is marketed in a package containing 1 or 5 syringes*.

*Not all pack sizes may be available.

Manufacturer: Amgen Europe B.V., Breda, the Netherlands.

Registration Holder: Amgen Europe B.V., P.O. BOX 53313, Tel - Aviv.

This leaflet was checked and approved by the Ministry of Health in August 2015 and was updated according to

the guidelines of the Ministry of Health in May 2019.

Registration number of the medicine in the National Drugs Registry at the Ministry of Health

Neupogen 30 MU pre-filled syringe: 117 22 29875

Neupogen 48 MU pre-filled syringe: 117 21 29876

Neupogen 30 MU vials: 058 31 27318

INSTRUCTIONS FOR SUBCUTANEOUS SELF-INJECTION OF NEUPOGEN

PRE-FILLED SYRINGE:

Instructions for injecting:

Neupogen 30 MU

p

re-filled syringe

Neupogen 48 MU pre-filled syringe

This section contains information on how to give an injection of Neupogen pre-filled syringe.

Important: do not try to give yourself an injection unless you have received training from your doctor or nurse.

Injecting

Neupogen

vial is done by a healthcare professional staff only.

Neupogen

is injected into the tissue just under the skin.

This is known as a subcutaneous injection.

Equipment that you need

To give yourself a subcutaneous injection you will need:

a new pre-filled syringe of Neupogen,

alcohol wipes or similar.

What do I do before I give myself a subcutaneous injection of Neupogen?

Remove one tray containing a syringe from the refrigerator and leave at room temperature for

approximately 30 minutes or hold gently in your hand for a few minutes. This will make the injection

more comfortable. Do not warm Neupogen in any other way (for example, do not warm it in a

microwave or in hot water).

Do not shake the pre-filled syringe.

Place the tray in your hand and peel the paper off the tray.

Flip the tray to place the pre-filled syringe onto your palm.

Do not remove the needle cover until you are ready to inject.

Check the expiry date on the pre-filled syringe label (EXP). Do not use it if the date has passed the last

day of the month shown.

Check the appearance of Neupogen. It must be a clear and colorless liquid. If there is discoloration,

cloudiness or particles in it, you must not use it.

Wash your hands thoroughly.

Find a comfortable, well-lit, clean surface and put all the equipment you need within reach.

How do I prepare my Neupogen injection?

Before you inject Neupogen you must do the following:

To avoid bending the needle, securely grasp the pre-filled syringe by the

glass barrel. Gently pull the cover from the needle without twisting as

shown in pictures 1 and 2.

Do not touch the needle or push the plunger.

You may notice a small air bubble in the pre-filled syringe. You do not

have to remove the air bubble before injecting. Injecting the solution with

the air bubble is harmless.

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You can now use the pre-filled syringe.

Where do I give my injection?

The best places to inject are the top of your thighs and the abdomen. If someone else is

injecting you, they can also use the back of your arms.

You may change the injection site if you notice the area is red or sore.

How do I give my injection?

Disinfect your skin by using an alcohol wipe and pinch (without squeezing) the skin between your thumb

and forefinger.

Put the needle fully into the skin as shown by your nurse or doctor.

Push the plunger with a slow constant pressure, always keeping your skin pinched, until the syringe is

empty.

Remove the needle and let go of your skin.

If you notice a spot of blood you may gently dab it away with a cotton ball or tissue. Do not rub the

injection site. If needed, you may cover the injection site with a plaster.

Only use each syringe for one injection. Do not use any Neupogen that may be left in the syringe.

Remember: if you have any problems, please do not be afraid to ask your doctor or nurse for help and advice.

Disposing of used syringes

Do not put the cover back on used needles, as you may accidentally prick yourself.

Keep used syringes out of the sight and reach of children.

Syringes should not be thrown out in the household rubbish. Your pharmacist will know how to dispose

of used syringes or syringes no longer needed.

The content of this leaflet was approved by the Ministry of Health in August 2015 and updated according to

the guidelines of the Ministry of Health in May 2019.

Neupogen

Filgrastim

1.

NAME OF THE MEDICINAL PRODUCT

Neupogen 30 MU vials (0.3 mg/ml) solution for injection in vials

Neupogen 30 MU pre-filled syringe (0.6 mg/ml) solution for injection in a pre-filled syringe

Neupogen 48 MU pre-filled syringe (0.96 mg/ml) solution for injection in a pre-filled syringe

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Neupogen 30 MU vials:

Each vial contains 30 million units (300 micrograms (µg)) of filgrastim in 1 ml (0.3 mg/ml).

Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced by r-DNA

technology in E. coli (K12).

Excipient with known effect:

Each ml of solution contains 0.023 to 0.051 mg sodium and 50 mg sorbitol.

Neupogen 30 MU pre-filled syringe:

Each pre-filled syringe contains 30 million units (MU)/300 micrograms (µg) of filgrastim in 0.5 ml

(0.6 mg/ml).

Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced by r-DNA

technology in E. coli (K12).

Excipient with known effect:

Each pre-filled syringe contains 0.0175 to 0.026 mg/0.5 ml (or 0.035 to 0.052 mg/ml) sodium and 25 mg (or

50 mg/ml) of sorbitol.

Neupogen 48 MU pre-filled syringe:

Each pre-filled syringe contains 48 million units (MU)/480 micrograms (

g) of filgrastim in 0.5 ml

(0.96 mg/ml).

Filgrastim (recombinant methionyl human granulocyte-colony stimulating factor) is produced by r-DNA

technology in E. coli (K12).

Excipient with known effect:

Each pre-filled syringe contains 0.0175 to 0.026 mg/0.5 ml (or 0.035 to 0.052 mg/ml) sodium and 25 mg (or

50 mg/ml) of sorbitol.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Neupogen 30 MU vials:

Solution for injection in a vial.

Concentrate for solution for infusion in a vial.

Neupogen 30 MU and 48 MU pre-filled syringe:

Solution for injection in a pre-filled syringe.

Concentrate for solution for infusion in a pre-filled syringe.

Clear, colorless solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

- Reduction in the duration and severity of neutropenia in patients treated with highly myelosuppressive

chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic

syndromes).

- Reduction in the duration of neutropenia in patients undergoing high-dose cytotoxic chemotherapy

followed by bone marrow transplantation.

- In children or adults with severe congenital neutropenia, cyclic neutropenia or idiopathic neutropenia, a

history of clinically important infections within the last 12 months and three documented episodes of

neutropenia (with an ANC < 5 x 1000000000), long-term administration of Neupogen is indicated to

increase neutrophil counts and to reduce infections.

- Neupogen is indicated for the mobilization of autologous peripheral blood progenitor cells alone or

following myelosuppressive chemotherapy and the mobilization of peripheral blood progenitor cells in

normal donors (allogeneic PBPC).

4.2

Posology and method of administration

Neupogen therapy should only be given in collaboration with an oncology center which has experience in

G-CSF treatment and hematology and has the necessary diagnostic facilities. The mobilization and apheresis

procedures should be performed in collaboration with an oncology-hematology center with acceptable

experience in this field and where the monitoring of hematopoietic progenitor cells can be correctly

performed.

Myelosuppressive chemotherapy

Posology

The recommended dose of Neupogen is 0.5 MU (5 µg)/kg/day. The first dose of Neupogen should be

administered at least 24 hours after cytotoxic chemotherapy. In randomized clinical trials, a subcutaneous

dose of 230 µg/m

/day (4.0 to 8.4 µg/kg/day) was used.

Daily dosing with Neupogen should continue until the expected neutrophil nadir is passed and the neutrophil

count has recovered to the normal range. Following established chemotherapy for solid tumors, lymphomas,

and lymphoid leukemia, it is expected that the duration of treatment required to fulfill these criteria will be

up to 14 days. Following induction and consolidation treatment for acute myeloid leukemia the duration of

treatment may be substantially longer (up to 38 days) depending on the type, dose and schedule of cytotoxic

chemotherapy used.

In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is typically seen 1 to

2 days after initiation of Neupogen therapy. However, for a sustained therapeutic response, Neupogen

therapy should not be discontinued before the expected nadir has passed and the neutrophil count has

recovered to the normal range. Premature discontinuation of Neupogen therapy, prior to the time of the

expected neutrophil nadir, is not recommended.

Method of administration

Neupogen may be given as a daily subcutaneous injection or as a daily intravenous infusion diluted in 5%

glucose solution given over 30 minutes (see section 6.6). The subcutaneous route is preferred in most cases.

There is some evidence from a study of single dose administration that intravenous dosing may shorten the

duration of effect. The clinical relevance of this finding to multiple dose administration is not clear. The

choice of route should depend on the individual clinical circumstance.

In patients treated with high-dose cytotoxic chemotherapy followed by bone marrow transplantation

Posology

The recommended starting dose of Neupogen is 1.0 MU (10 µg)/kg/day.

The first dose of Neupogen should be administered at least 24 hours after cytotoxic chemotherapy and at

least 24 hours after bone marrow infusion.

Once the neutrophil nadir has been passed, the daily dose of Neupogen should be titrated against the

neutrophil response as follows:

Neutrophil Count

Neupogen Dose Adjustment

> 1.0 x 10

/l for 3 consecutive days

Reduce to 0.5 MU (5 µg)/kg/day

Then, if ANC remains > 1.0 x 10

/l for 3 more

consecutive days

Discontinue Neupogen

If the ANC decreases to < 1.0 x 10

/l during the treatment period the dose of Neupogen should be

re-escalated according to the above steps

ANC = absolute neutrophil count

Method of administration

Neupogen may be given as a 30 minute or 24 hour intravenous infusion or 1.0 MU (10 µg)/kg/day given by

continuous 24 hour subcutaneous infusion. Neupogen should be diluted in 20 ml of 5% glucose solution (see

section 6.6).

For the mobilization of PBPCs in patients undergoing myelosuppressive or myeloablative therapy followed

by autologous PBPC transplantation

Posology

The recommended dose of Neupogen for PBPC mobilization when used alone is 1.0 MU (10 µg)/kg/day for

5 to 7 consecutive days. Timing of leukapheresis: one or two leukapheresis on days 5 and 6 are often

sufficient. In other circumstances, additional leukapheresis may be necessary. Neupogen dosing should be

maintained until the last leukapheresis.

The recommended dose of Neupogen for PBPC mobilization after myelosuppressive chemotherapy is

0.5 MU (5 µg)/kg/day from the first day after completion of chemotherapy until the expected neutrophil

nadir is passed and the neutrophil count has recovered to the normal range. Leukapheresis should be

performed during the period when the ANC rises from < 0.5 x 10

/l to > 5.0 x 10

/l. For patients who have

not had extensive chemotherapy, one leukapheresis is often sufficient. In other circumstances, additional

leukapheresis are recommended.

Method of administration

Neupogen for PBPC mobilization when used alone:

Neupogen may be given as a 24 hour subcutaneous continuous infusion or subcutaneous injection. For

infusions Neupogen should be diluted in 20 ml of 5% glucose solution (see section 6.6).

Neupogen for PBPC mobilization after myelosuppressive chemotherapy:

Neupogen should be given by subcutaneous injection.

For the mobilization of PBPCs in normal donors prior to allogeneic PBPC transplantation

Posology

For PBPC mobilization in normal donors, Neupogen should be administered at 1.0 MU (10 µg)/kg/day for 4

to 5 consecutive days. Leukapheresis should be started at day 5 and continued until day 6 if needed in order

to collect 4 x 10

CD34

cells/kg recipient body weight.

Method of administration

Neupogen should be given by subcutaneous injection.

In patients with severe chronic neutropenia (SCN)

Posology

Congenital neutropenia: the recommended starting dose is 1.2 MU (12 µg)/kg/day, as a single dose or in

divided doses.

Idiopathic or cyclic neutropenia: the recommended starting dose is 0.5 MU (5 µg)/kg/day, as a single dose or

in divided doses.

Dose adjustment: Neupogen should be administered daily by subcutaneous injection until the neutrophil

count has reached and can be maintained at more than 1.5 x 10

/l. When the response has been obtained the

minimal effective dose to maintain this level should be established. Long-term daily administration is

required to maintain an adequate neutrophil count. After one to two weeks of therapy, the initial dose may

be doubled or halved depending upon the patient’s response. Subsequently the dose may be individually

adjusted every 1 to 2 weeks to maintain the average neutrophil count between 1.5 x 10

/l and 10 x 10

/l. A

faster schedule of dose escalation may be considered in patients presenting with severe infections. In clinical

trials, 97% of patients who responded had a complete response at doses ≤ 24 µg/kg/day. The long-term

safety of Neupogen administration above 24 µg/kg/day in patients with SCN has not been established.

Method of administration

Congenital, idiopathic or cyclic neutropenia: Neupogen should be given by subcutaneous injection.

Older people

Clinical trials with Neupogen have included a small number of elderly patients but special studies have not

been performed in this group and therefore specific dosage recommendations cannot be made.

Patients with renal impairment

Studies of Neupogen in patients with severe impairment of renal or hepatic function demonstrate that it

exhibits a similar pharmacokinetic and pharmacodynamic profile to that seen in normal individuals. Dose

adjustment is not required in these circumstances.

Pediatric use in the SCN and cancer settings

Sixty-five percent of the patients studied in the SCN trial program were under 18 years of age. The efficacy

of treatment was clear for this age group, which included most patients with congenital neutropenia. There

were no differences in the safety profiles for pediatric patients treated for SCN.

Data from clinical studies in pediatric patients indicate that the safety and efficacy of Neupogen are similar

in both adults and children receiving cytotoxic chemotherapy.

The dosage recommendations in pediatric patients are the same as those in adults receiving

myelosuppressive cytotoxic chemotherapy.

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

Special warning and precautions across indications

Hypersensitivity

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

reported in patients treated with Neupogen. Permanently discontinue Neupogen in patients with clinically

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

filgrastim or pegfilgrastim.

Pulmonary adverse

effects

Pulmonary adverse effects, in particular interstitial lung disease, have been reported after G-CSF

administration. Patients with a recent history of lung infiltrates or pneumonia may be at higher risk. The

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

pulmonary infiltrates and deterioration in pulmonary function may be preliminary signs of acute respiratory

distress syndrome (ARDS). Neupogen should be discontinued and appropriate treatment given.

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, which can be life-threatening if treatment is delayed, has been reported after

granulocyte-colony stimulating factor administration, and is characterized by hypotension,

hypoalbuminemia, edema and hemoconcentration. 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 have been reported

patients

and normal donors following administration of Neupogen.

Some cases of splenic rupture

were

fatal.

Therefore,

spleen size should be carefully monitored (e.g.

clinical examination,

ultrasound).

diagnosis

of splenic rupture should be considered in donors and/or patients reporting left

upper

abdominal

shoulder tip pain.

Dose reductions of Neupogen have been noted to slow or stop

progression of

splenic enlargement

in patients with severe chronic neutropenia,

and in 3% of patients

splenectomy was

required.

Malignant cell growth

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.

Myelodysplastic syndrome or Chronic myeloid

leukemia

The safety and efficacy of Neupogen administration in patients with myelodysplastic syndrome, or chronic

myelogenous leukemia have not been established.

Neupogen is not indicated for use in these conditions.

Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid

leukemia from acute myeloid leukemia.

Acute myeloid

leukemia

In view of limited safety and efficacy data in patients with secondary AML, Neupogen should be

administered with caution. The safety and efficacy of Neupogen administration in de novo AML patients

aged < 55 years with good cytogenetics (t(8;21), t(15;17), and in v(16)) have not been established.

Thrombocytopenia

Thrombocytopenia has been reported in patients receiving Neupogen.

Platelet counts should

monitored

closely,

especially during the first few weeks of Neupogen therapy.

Consideration

should be

given to

temporary discontinuation or dose reduction of Neupogen in patients with severe

chronic

neutropenia who

develop thrombocytopenia (platelet count < 100 x

/l).

Leukocytosis

White blood cell counts of 100 x 10

/l or greater have been observed in less than 5% of cancer patients

receiving Neupogen at doses above 0.3 MU/kg/day (3 µg/kg/day). No undesirable effects directly

attributable to this degree of leukocytosis have been reported. However, in view of the potential risks

associated with severe leukocytosis, a white blood cell count should be performed at regular intervals during

Neupogen therapy. If leukocyte counts exceed 50 x 10

/l after the expected nadir, Neupogen should be

discontinued immediately. When administered for PBPC mobilization, Neupogen should be discontinued or

its dosage should be reduced if the leukocyte counts rise to > 70 x 10

Immunogenicity

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

against filgrastim is generally low. Binding antibodies do occur as expected with all biologics; however,

they have not been associated with neutralizing 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 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. See also section 4.8.

Special warnings and precautions associated with co-morbidities

Special precautions in sickle cell trait and sickle cell disease

Sickle cell crises, in some cases fatal, have been reported with the use of Neupogen in patients with sickle

cell trait or sickle cell disease. Physicians should use caution when prescribing Neupogen in patients with

sickle cell trait or sickle cell disease.

Osteoporosis

Monitoring of bone density may be indicated in patients with underlying osteoporotic bone diseases who

undergo continuous therapy with Neupogen for more than 6 months.

Special precautions in cancer patients

Neupogen should not be used to increase the dose of cytotoxic chemotherapy beyond established dosage

regimens.

Risks associated with increased doses of chemotherapy

Special caution should be used when treating patients with high-dose chemotherapy, because improved

tumor outcome has not been demonstrated and intensified doses of chemotherapeutic agents may lead to

increased toxicities including cardiac, pulmonary, neurologic, and dermatologic effects (please refer to the

prescribing information of the specific chemotherapy agents used).

Effect of chemotherapy on erythrocytes and thrombocytes

Treatment with Neupogen alone does not preclude thrombocytopenia and anemia due to myelosuppressive

chemotherapy. Because of the potential of receiving higher doses of chemotherapy (e.g. full doses on the

prescribed schedule) the patient may be at greater risk of thrombocytopenia and anemia. Regular monitoring

of platelet count and hematocrit is recommended. Special care should be taken when administering single or

combination chemotherapeutic agents which are known to cause severe thrombocytopenia.

The use of Neupogen mobilized PBPCs has been shown to reduce the depth and duration of

thrombocytopenia following myelosuppressive or myeloablative chemotherapy.

Other special precautions

The effects of Neupogen in patients with substantially reduced myeloid progenitors have not been studied.

Neupogen acts primarily on neutrophil precursors to exert its effect in elevating neutrophil counts. Therefore

in patients with reduced precursors neutrophil response may be diminished (such as those treated with

extensive radiotherapy or chemotherapy, or those with bone marrow infiltration by tumor).

Vascular disorders, including veno-occlusive disease and fluid volume disturbances, have been reported

occasionally in patients undergoing high-dose chemotherapy followed by transplantation.

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow

transplantation (see sections 4.8 and 5.1).

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been

associated with transient abnormal bone scans. This should be considered when interpreting bone-imaging

results.

Special precautions in patients undergoing PBPC mobilization

Mobilization

There are no prospectively randomized comparisons of the two recommended mobilization methods

(Neupogen alone, or in combination with myelosuppressive chemotherapy) within the same patient

population. The degree of variation between individual patients and between laboratory assays of CD34

cells mean that direct comparison between different studies is difficult. It is therefore difficult to recommend

an optimum method. The choice of mobilization method should be considered in relation to the overall

objectives of treatment for an individual patient.

Prior exposure to cytotoxic agents

Patients who have undergone very extensive prior myelosuppressive therapy may not show sufficient

mobilization of PBPC to achieve the recommended minimum yield (≥ 2.0 x 10

CD34

cells/kg) or

acceleration of platelet recovery, to the same degree.

Some cytotoxic agents exhibit particular toxicities to the hematopoietic progenitor pool, and may adversely

affect progenitor mobilization. Agents such as melphalan, carmustine (BCNU), and carboplatin, when

administered over prolonged periods prior to attempts at progenitor mobilization may reduce progenitor

yield. However, the administration of melphalan, carboplatin or BCNU together with Neupogen, has been

shown to be effective for progenitor mobilization. When a PBPC transplantation is envisaged it is advisable

to plan the stem cell mobilization procedure early in the treatment course of the patient. Particular attention

should be paid to the number of progenitors mobilized in such patients before the administration of

high-dose chemotherapy. If yields are inadequate, as measured by the criteria above, alternative forms of

treatment, not requiring progenitor support should be considered.

Assessment of progenitor cell yields

In assessing the number of progenitor cells harvested in patients treated with Neupogen, particular attention

should be paid to the method of quantitation. The results of flow cytometric analysis of CD34

cell numbers

vary depending on the precise methodology used and recommendations of numbers based on studies in other

laboratories need to be interpreted with caution.

Statistical analysis of the relationship between the number of CD34

cells re-infused and the rate of platelet

recovery after high-dose chemotherapy indicates a complex but continuous relationship.

The recommendation of a minimum yields of ≥ 2.0 x 10

CD34

cells/kg is based on published experience

resulting in adequate hematologic reconstitution. Yields in excess of this appear to correlate with more rapid

recovery, those below with slower recovery.

Special precautions in normal donors undergoing PBPC mobilization

Mobilization of PBPC does not provide a direct clinical benefit to normal donors and should only be

considered for the purposes of allogeneic stem cell transplantation.

PBPC mobilization should be considered only in donors who meet normal clinical and laboratory eligibility

criteria for stem cell donation with special attention to hematological values and infectious disease.

The safety and efficacy of Neupogen have not been assessed in normal donors < 16 years or > 60 years.

Transient thrombocytopenia (platelets < 100 x 10

/l) following filgrastim administration and leukapheresis

was observed in 35% of subjects studied. Among these, two cases of platelets < 50 x 10

/l were reported and

attributed to the leukapheresis procedure.

If more than one leukapheresis is required, particular attention should be paid to donors with platelets

< 100 x 10

/l prior to leukapheresis; in general apheresis should not be performed if platelets < 75 x 10

Leukapheresis should not be performed in donors who are anticoagulated or who have known defects in

hemostasis.

Donors who receive G-CSFs for PBPC mobilization should be monitored until hematological indices return

to normal.

Transient cytogenetic abnormalities have been observed in normal donors following G-CSF use. The

significance of these changes is unknown. Nevertheless, a risk of promotion of a malignant myeloid clone

cannot be excluded. It is recommended that the apheresis center perform a systematic record and tracking of

the stem cell donors for at least 10 years to ensure monitoring of long-term safety.

Special precautions in recipients of allogeneic PBPCs mobilized with Neupogen

Current data indicate that immunological interactions between the allogeneic PBPC graft and the recipient

may be associated with an increased risk of acute and chronic GvHD when compared with bone marrow

transplantation.

Special precautions in SCN patients

Neupogen should not be administered to patients with severe congenital neutropenia who develop leukemia

or have evidence of leukemic evolution.

Blood cell counts

Other blood cell changes occur, including anemia and transient increases in myeloid progenitors, which

require close monitoring of cell counts.

Transformation to leukemia or myelodysplastic syndrome

Special care should be taken in the diagnosis of SCNs to distinguish them from other hematopoietic

disorders such as aplastic anemia, myelodysplasia, and myeloid leukemia. Complete blood cell counts with

differential and platelet counts, and an evaluation of bone marrow morphology and karyotype should be

performed prior to treatment.

There was a low frequency (approximately 3%) of myelodysplastic syndromes (MDS) or leukemia in

clinical trial patients with SCN treated with Neupogen. This observation has only been made in patients with

congenital neutropenia. MDS and leukemias are natural complications of the disease and are of uncertain

relation to Neupogen therapy. A subset of approximately 12% of patients who had normal cytogenetic

evaluations at baseline were subsequently found to have abnormalities, including monosomy 7, on routine

repeat evaluation. It is currently unclear whether long-term treatment of patients with SCN will predispose

patients to cytogenetic abnormalities, MDS or leukemic transformation. It is recommended to perform

morphologic and cytogenetic bone marrow examinations in patients at regular intervals (approximately every

12 months).

Other special precautions

Causes of transient neutropenia, such as viral infections should be excluded.

Hematuria was common and proteinuria occurred in a small number of patients. Regular urinalysis should

be performed to monitor these events.

The safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.

All patients

The needle cover of the pre-filled syringe may contain dry natural rubber (a derivative of latex), which may

cause allergic reactions.

Neupogen contains sorbitol (E420).

Patients with hereditary fructose intolerance (HFI) must not be given

this medicine unless strictly necessary.

Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose

intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may be life-threatening and

should be contraindicated in this population unless there is an overwhelming clinical need and no alternatives

are available.

A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this

medicinal product.

Neupogen contains less than 1 mmol (23 mg) sodium per 0.3/ 0.6/ 0.96 mg/ml, that is to say essentially

'sodium free'.

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.

4.5

Interaction with other medicinal products and other forms of interaction

The safety and efficacy of Neupogen given on the same day as myelosuppressive cytotoxic chemotherapy

have not been definitively established. In view of the sensitivity of rapidly dividing myeloid cells to

myelosuppressive cytotoxic chemotherapy, the use of Neupogen is not recommended in the period from

24 hours before to 24 hours after chemotherapy. Preliminary evidence from a small number of patients

treated concomitantly with Neupogen and 5-Fluorouracil indicates that the severity of neutropenia may be

exacerbated.

Possible interactions with other hematopoietic growth factors and cytokines have not yet been investigated in

clinical trials.

Since lithium promotes the release of neutrophils, lithium is likely to potentiate the effect of Neupogen.

Although this interaction has not been formally investigated, there is no evidence that such an interaction is

harmful.

4.6

Fertility, pregnancy and lactation

Pregnancy

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

have shown reproductive toxicity.

An increased incidence of embryo-loss has been observed in rabbits at

high multiples of the clinical exposure and in the presence of maternal toxicity (see section 5.3).

There are

reports in the literature where the transplacental passage of filgrastim in pregnant women has been

demonstrated.

Neupogen is not recommended during pregnancy.

Breast-feeding

It is unknown whether filgrastim/metabolites are excreted 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 Neupogen therapy taking into account the benefit of breast-feeding for the child

and the benefit of therapy for the woman.

Fertility

Filgrastim did not affect reproductive performance or fertility in male or female rats (see section 5.3).

4.7

Effects on ability to drive and use machines

Neupogen may have a minor influence on the ability to drive and use machines.

Dizziness may occur

following the administration of Neupogen (see section 4.8).

4.8

Undesirable effects

Summary of the safety profile

The most serious adverse reactions that may occur during Neupogen treatment include: anaphylactic

reaction, serious pulmonary adverse events (including interstitial pneumonia and ARDS), capillary leak

syndrome, severe splenomegaly/splenic rupture, transformation to myelodysplastic syndrome or leukemia in

SCN patients, GvHD in patients receiving allogeneic bone marrow transfer or peripheral blood cell

progenitor cell transplant and sickle cell crisis in patients with sickle cell disease.

The most commonly reported adverse reactions are pyrexia, musculoskeletal pain (which includes bone pain,

back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, neck

pain), anemia, vomiting, and nausea.

In clinical trials in cancer patients musculoskeletal pain was mild or

moderate in 10%, and severe in 3% of patients.

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

(≥ 1/1000 to

< 1/100)

Rare

(≥ 1/10,000 to

< 1/1000)

Very rare

(< 1/10,000)

Infections and

infestations

Sepsis

Bronchitis

Upper respiratory

tract infection

Urinary tract

infection

Blood and

lymphatic

system

disorders

Thrombocytopenia

Anemia

Splenomegaly

Hemoglobin

decreased

Leukocytosis

Splenic rupture

Sickle cell

anemia with

crisis

Immune system

disorders

Hypersensitivity

Drug

hypersensitivity

Graft versus Host

Disease

Anaphylactic

reaction

Metabolism and

nutrition

disorders

Decreased

appetite

Blood lactate

dehydrogenase

increased

Hyperuricemia

Blood uric acid

increased

Blood glucose

decreased

Pseudogout

(Chondrocalcin

osis

Pyrophosphate)

Fluid volume

disturbances

Psychiatric

disorders

Insomnia

Nervous system

disorders

Headache

Dizziness

Hypoesthesia

Paresthesia

Vascular

disorders

Hypertension

Hypotension

Veno-occlusive

disease

Capillary leak

syndrome

Aortitis

Respiratory,

thoracic and

mediastinal

disorders

Hemoptysis

Dyspnea

Cough

Oropharyngeal

pain

a, e

Epistaxis

Acute respiratory

distress

syndrome

Respiratory

failure

Pulmonary

edema

Pulmonary

hemorrhage

Interstitial lung

disease

Lung infiltration

Hypoxia

MedDRA

system organ

class

Adverse reactions

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)

Gastrointestinal

disorders

Diarrhea

a, e

Vomiting

a, e

Nausea

Oral pain

Constipation

Hepatobiliary

disorders

Hepatomegaly

Blood alkaline

phosphatase

increased

Aspartate

aminotransferase

increased

Gamma-glutamyl

transferase

increased

Skin and

subcutaneous

tissue disorders

Alopecia

Rash

Erythema

Rash

maculopapular

Cutaneous

vasculitis

Sweets

syndrome

(acute febrile

neutrophilic

dermatosis)

Musculoskeletal

and connective

tissue disorders

Musculoskeletal

pain

Muscle spasms

Osteoporosis

Bone density

decreased

Exacerbation of

rheumatoid

arthritis

Renal and

urinary

disorders

Dysuria

Hematuria

Proteinuria

Glomeruloneph

ritis

Urine

abnormality

General

disorders and

administration

site conditions

Fatigue

Mucosal

inflammation

Pyrexia

Chest pain

Pain

Asthenia

Malaise

Edema

peripheral

Injection site

reaction

Injury,

poisoning and

procedural

complications

Transfusion

reaction

See section c (Description of selected adverse reactions)

There have been reports of GvHD and fatalities in patients after allogeneic bone marrow transplantation (see section c)

Includes bone pain, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain,

neck pain

Cases were observed in the post-marketing setting in patients undergoing bone marrow transplant or PBPC

mobilization

Adverse events with higher incidence in Neupogen patients compared to placebo and associated with the sequelae of

the underlying malignancy or cytotoxic chemotherapy

Description of selected adverse reactions

Hypersensitivity

Hypersensitivity-type reactions including anaphylaxis, rash, urticaria, angioedema, dyspnea and hypotension

occurring on initial or subsequent treatment have been reported in clinical studies and in post-marketing

experience. Overall, reports were more common after IV administration. In some cases, symptoms have

recurred with rechallenge, suggesting a causal relationship. Neupogen should be permanently discontinued

in patients who experience a serious allergic reaction.

Pulmonary adverse events

In clinical studies and the post-marketing setting pulmonary adverse effects including interstitial lung

disease, pulmonary edema, and lung infiltration have been reported in some cases with an outcome of

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

Splenomegaly and Splenic rupture

Cases of splenomegaly and splenic rupture have been reported following administration of filgrastim. Some

cases of splenic rupture were fatal (see section 4.4).

Capillary leak syndrome

Cases of capillary leak syndrome have been reported with granulocyte-colony stimulating factor use. These

have generally occurred in patients with advanced malignant diseases, sepsis, taking multiple chemotherapy

medications or undergoing apheresis (see section 4.4).

Cutaneous vasculitis

Cutaneous vasculitis has been reported in patients treated with Neupogen. The mechanism of vasculitis in

patients receiving Neupogen is unknown. During long-term use cutaneous vasculitis has been reported in 2%

of SCN patients.

Leukocytosis

Leukocytosis (WBC > 50 x 10

/l) was observed in 41% of normal donors and transient thrombocytopenia

(platelets < 100 x 10

/l) following filgrastim and leukapheresis was observed in 35% of donors (see

section 4.4).

Sweets syndrome

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

Neupogen.

Pseudogout (chondrocalcinosis pyrophosphate)

Pseudogout

(chondrocalcinosis pyrophosphate)

has been reported in patients with cancer treated with

Neupogen.

GvHD

There have been reports of GvHD and fatalities in patients receiving G-CSF after allogeneic bone marrow

transplantation (see sections 4.4 and 5.1).

Pediatric population

Data from clinical studies in pediatric patients indicate that the safety and efficacy of Neupogen are similar

in both adults and children receiving cytotoxic chemotherapy suggesting no age-related differences in the

pharmacokinetics of filgrastim. The only consistently reported adverse event was musculoskeletal pain‚

which is no different from the experience in the adult population.

There is insufficient data to further evaluate Neupogen use in pediatric subjects.

Other special populations

Geriatric use

No overall differences in safety or effectiveness were observed between subjects over 65 years of age

compared to younger adult (> 18 years of age) subjects receiving cytotoxic chemotherapy and clinical

experience has not identified differences in the responses between elderly and younger adult patients. There

is insufficient data to evaluate Neupogen use in geriatric subjects for other approved Neupogen indications.

Pediatric SCN patients

Cases of decreased bone density and osteoporosis have been reported in pediatric patients with severe

chronic neutropenia receiving chronic treatment with Neupogen.

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

4.9

Overdose

The effects of Neupogen overdosage have not been established. Discontinuation of Neupogen therapy

usually results in a 50% decrease in circulating neutrophils within 1 to 2 days, with a return to normal levels

in 1 to 7 days.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Cytokines, ATC Code: L03AA02

Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from

the bone marrow. Neupogen containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral

blood neutrophil counts within twenty-four hours, with minor increases in monocytes. In some SCN patients

filgrastim can also induce a minor increase in the number of circulating eosinophils and basophils relative to

baseline; some of these patients may present with eosinophilia or basophilia already prior to treatment.

Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced in

response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and

phagocytic function. Following termination of filgrastim therapy, circulating neutrophil counts decrease by

50% within 1 to 2 days, and to normal levels within 1 to 7 days.

Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the

incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim

significantly reduces the durations of febrile neutropenia, antibiotic use and hospitalization after induction

chemotherapy for acute myelogenous leukemia or myeloablative therapy followed by bone marrow

transplantation.

The incidence of fever and documented infections were not reduced in either setting. The

duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow

transplantation.

Use of filgrastim, either alone, or after chemotherapy, mobilizes hematopoietic progenitor cells into the

peripheral blood. These autologous PBPCs may be harvested and infused after high-dose cytotoxic therapy,

either in place of, or in addition to bone marrow transplantation. Infusion of PBPC accelerates

hematopoietic recovery reducing the duration of risk for hemorrhagic complications and the need for platelet

transfusions.

Recipients of allogeneic PBPCs mobilized with Neupogen experienced significantly more rapid

hematological recovery, leading to a significant decrease in time to unsupported platelet recovery when

compared with allogeneic bone marrow transplantation.

One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation

in patients with acute leukemias suggested an increase in the risk of GvHD, treatment-related mortality

(TRM) and mortality when G-CSF was administered. In a separate retrospective International study in

patients with acute and chronic myelogenous leukemias, no effect on the risk of GvHD, TRM and mortality

was seen. A meta-analysis of allogeneic transplant studies, including the results of nine prospective

randomized trials, 8 retrospective studies and 1 case-controlled study, did not detect an effect on the risks of

acute GvHD, chronic GvHD or early treatment-related mortality.

Relative Risk (95% CI) of GvHD and TRM

Following Treatment with G-CSF after Bone Marrow Transplantation

Publication

Period of

Study

N

Acute

Grade II-IV GvHD

Chronic

GvHD

TRM

Meta-Analysis

(2003)

1986-2001

1198

1.08

(0.87, 1.33)

1.02

(0.82, 1.26)

0.70

(0.38, 1.31)

European

Retrospective

Study (2004)

1992-2002

1789

1.33

(1.08, 1.64)

1.29

(1.02, 1.61)

1.73

(1.30, 2.32)

International

Retrospective

Study (2006)

1995-2000

2110

1.11

(0.86, 1.42)

1.10

(0.86, 1.39)

1.26

(0.95, 1.67)

Analysis includes studies involving BM transplant during this period; some studies used GM-CSF

Analysis includes patients receiving BM transplant during this period

Use of filgrastim for the mobilization of PBPCs in normal donors prior to allogeneic PBPC transplantation

In normal donors, a 10 µg/kg/day dose administered subcutaneously for 4 to 5 consecutive days allows a

collection of ≥ 4 x 10

CD34

cells/kg recipient body weight in the majority of the donors after two

leukaphereses.

Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic

neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a reduction of

infection and related events.

As with other hematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human

endothelial cells.

5.2

Pharmacokinetic properties

Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous and

intravenous administration. The serum elimination half-life of filgrastim is approximately 3.5 hours, with a

clearance rate of approximately 0.6 ml/min/kg. Continuous infusion with Neupogen over a period of up to

28 days, in patients recovering from autologous bone marrow transplantation, resulted in no evidence of drug

accumulation and comparable elimination half-lives. There is a positive linear correlation between the dose

and the serum concentration of filgrastim, whether administered intravenously or subcutaneously. Following

subcutaneous administration of recommended doses, serum concentrations were maintained above 10 ng/ml

for 8 to 16 hours. The volume of distribution in blood is approximately 150 ml/kg.

5.3

Preclinical safety data

Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed changes

attributable to the expected pharmacological actions including increases in leukocytes, myeloid hyperplasia

in bone marrow, extramedullary granulopoiesis and splenic enlargement.

These changes all reversed after

discontinuation of treatment.

Effects of filgrastim on prenatal development have been studied in rats and rabbits. Intravenous

(80 µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was maternally

toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size and

fetal weight were observed.

Based on reported data for another filgrastim product similar to Neupogen, comparable findings plus

increased fetal malformations were observed at 100 µg/kg/day, a maternally toxic dose which corresponded

to a systemic exposure of approximately 50-90 times the exposures observed in patients treated with the

clinical dose of 5 µg/kg/day. The no observed adverse effect level for embryo-fetal toxicity in this study was

10 µg/kg/day, which corresponded to a systemic exposure of approximately 3-5 times the exposures

observed in patients treated with the clinical dose.

In pregnant rats, no maternal or fetal toxicity was observed at doses up to 575 µg/kg/day. Offspring of rats

administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external

differentiation and growth retardation (≥ 20 µg/kg/day) and slightly reduced survival rate (100 µg/kg/day).

Filgrastim had no observed effect on the fertility of male or female rats.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Glacial acetic acid

Sodium hydroxide (1N) ad pH4

Sorbitol

Polysorbate 80

Water for Injections

6.2

Incompatibilities

Neupogen should not be diluted with saline solutions.

Diluted filgrastim may be adsorbed to glass and plastic materials.

This medicinal product must not be mixed with other products except those mentioned in section 6.6.

6.3

Shelf life

30 months.

Chemical and physical in-use stability of the diluted solution for infusion has been demonstrated for 24 hours

at 2°C to 8°C. From a microbiological point of view, the product should be used immediately. If not used

immediately, in-use storage times and conditions prior to use are the responsibility of the user and would

normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and

validated aseptic conditions.

6.4

Special precautions for storage

Store at 2°C to 8°C.

For storage conditions after dilution of the medicinal product, see section 6.3.

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

Do not freeze.

6.5

Nature and contents of container

Neupogen 30 MU vials

Package containing five vials of 1 ml Neupogen solution for injection.

The vials are made from type I glass with rubber stoppers.

Neupogen 30 MU and 48 MU pre-filled syringes

Package containing one or five pre-filled syringe(s) of 0.5 ml Neupogen solution for injection.

The pre-filled syringes are made from type I glass and have a permanently attached stainless steel needle in

the tip. The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) or

synthetic rubber. See section 4.4.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

If required, Neupogen may be diluted in 5% glucose.

Dilution to a final concentration less than 0.2 MU (2 µg) per ml is not recommended at any time.

The solution should be visually inspected prior to use. Only clear solutions without particles should be used.

For patients treated with filgrastim diluted to concentrations below 1.5 MU (15 µg) per ml, human serum

albumin (HSA) should be added to a final concentration of 2 mg/ml.

Example: In a final injection volume of 20 ml, total doses of filgrastim less than 30 MU (300 µg) should be

given with 0.2 ml of 20% human albumin solution Ph. Eur. added.

Neupogen contains no preservative. In view of the possible risk of microbial contamination, Neupogen

pre-filled syringes and vials are for single use only.

When diluted in 5% glucose solution, Neupogen is compatible with glass and a variety of plastics including

PVC, polyolefin (a co-polymer of polypropylene and polyethylene) and polypropylene.

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

requirements.

7.

MANUFACTURER

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

8.

LICENSE HOLDER

Amgen Europe B.V.

P.O. BOX 53313

Tel - Aviv

9.

LICENSE NUMBERS

Neupogen 30 MU Vials 058 31 27318 00

Neupogen 30 MU PFS 117 22 29875 00

Neupogen 48 MU PFS 117 21 29876 00