ENBREL 50 MG SOLUTION FOR INJECTION

Directions for use:

Detailed instructions on how to prepare and inject –

see subsection “Instructions for preparing and

injecting”.

It is recommended to keep a diary to remember which

day(s) of the week you should inject Enbrel

®

.

If a higher dosage was accidentally injected, refer to

a doctor immediately. If a child accidentally swallowed

the medicine, immediately refer to a doctor or to a hospital

emergency room and bring the package of the medicine

with you.

If you forget to inject the Enbrel

®

dose at the scheduled

time, inject a dose as soon as you remember (if the next

scheduled dose is supposed to be given the next day, skip

the missed dose). Then continue to inject the medicine on

the usual days. If you did not remember to inject the dose

until the day that the next injection is due, do not inject a

double dose to make up for a missing dose.

Persist with the treatment as recommended by the

doctor.

If you stop using the medicine the symptoms of the

disease may return. Consult the doctor or pharmacist

regarding discontinuation of treatment.

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 further questions regarding use of the

medicine, consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Enbrel

may cause side

effects in some users. Do not be alarmed when reading

the list of side effects. You/the child may not suffer from

any of them.

Stop treatment and immediately refer to the doctor or

for medical assistance if you/the child experience any

of the following severe allergic symptoms:

Difficulty swallowing or breathing.

Swelling of the face, neck, hands or feet.

Nervousness or anxiety, rapid heart rate, sudden

redness of the skin and/or warm sensation.

Severe rash, severe itch or severe urticaria: an effect

characterized by red or pale, raised and itchy patches

on the skin.

Refer to the doctor immediately if you/the child

experience any of the following severe symptoms

which indicate rare side effects that can sometimes

be fatal:

Signs of serious infections, such as high fever that

may be accompanied by cough, shortness of breath,

chills, weakness, or a hot, red, tender, sore area on the

skin or joints.

Signs of blood disorders, such as bleeding, tendency

for subcutaneous hematomas or paleness.

Signs of nerve disorders, such as numbness or

tingling sensation, changes in vision, eye pain, or onset

of weakness in an arm or leg.

Signs of heart failure or worsening heart failure,

such as fatigue or shortness of breath during activity,

swelling in the ankles, a feeling of fullness in the neck or

abdomen, night-time shortness of breath or coughing,

bluish color of the nails or the lips.

Signs of cancer: Cancer can affect any part of the body

including the skin and blood, and possible signs will

depend on the type and location of the cancer.

These signs may include weight loss, fever, swelling

(with or without pain), persistent cough, presence of

lumps or growths on the skin.

Signs of autoimmune reactions (where antibodies

may harm normal tissues in the body) such as pain,

itching, weakness, and abnormal breathing, thinking,

sensation, or vision.

Signs of lupus or lupus-like syndrome, such as

weight changes, persistent rash, fever, joint or muscle

pain, or fatigue.

Signs of inflammation of the blood vessels, such as

pain, fever, redness or warmth of the skin, or itching.

Additional side effects

Very common side effects (may occur in more than

1 in 10 people):

Infections (including cold, sinusitis, bronchitis, urinary

tract infections, skin infections)

Injection site reactions (including bleeding, bruising,

redness, itching, pain, or swelling). These effects

are usually common at the beginning of treatment,

and their frequency usually declines after about one

month. Some patients have developed a reaction at

an injection site that was used before.

Common side effects (may occur in up to 1 in 10

people):

Allergic reactions

Fever

Rash

Itching

Antibodies directed against normal tissues.

Uncommon side effects (may occur in up to 1 in 100

people):

Serious infections (including pneumonia, deep-

skin infections, joint infections, blood infection, and

infections at various sites)

Worsening of congestive heart failure

Low red blood cell count

Low white blood cell count

Low neutrophil (a type of white blood cell) count

Low blood platelet count

Skin cancer - other than melanoma

Localized swelling of the skin (angioedema)

Hives (urticaria), an effect characterized by elevated

red or pale, and itchy skin patches

Eye inflammation

New or worsening psoriasis

Inflammation of the blood vessels affecting multiple

organs

Elevated liver function blood tests (in patients also

receiving methotrexate treatment, the frequency of

elevated liver function blood tests is common).

Rare side effects (may occur in up to 1 in 1,000

people):

Serious allergic reactions (including severe localized

swelling of the skin and wheezing)

Lymphoma (a type of blood cancer)

Leukemia (a cancer affecting the blood and bone

marrow)

Melanoma (a type of skin cancer)

Combined low platelet, white and red blood cell

count

Nervous system disorders (with severe muscle

weakness and symptoms and signs similar to those

of multiple sclerosis or of inflammation of the optic

nerve or spinal cord)

Tuberculosis

Onset of congestive heart failure

Seizures

Lupus or lupus-like syndrome (symptoms such as

persistent rash, fever, joint pain and tiredness)

Skin rash, which may lead to severe blistering and

peeling of the skin

lichenoid reactions (itchy reddish-purple rash and/or

white-gray threadlike lines on mucous membranes).

Inflammation of the liver caused by the body’s own

immune system (autoimmune hepatitis; in patients

also receiving methotrexate treatment, the frequency

is uncommon)

Immune system disorders that can affect the lungs,

skin and lymph nodes (sarcoidosis)

Inflammation or scarring of the lungs (in patients also

receiving methotrexate treatment, the side effect of

inflammation or scarring of the lungs is uncommon).

Very rare side effects (may occur in up to 1 in 10,000

people):

Failure of the bone marrow to produce essential blood

cells.

Side effects of unknown frequency:

Merkel cell carcinoma, a type of skin cancer

Excessive activity of white blood cells associated with

inflammation (macrophage activation syndrome)

Recurrence of hepatitis B

Worsening of a condition called dermatomyositis

(muscle inflammation and weakness accompanied

by skin rash).

Side effects in children and adolescents

Side effects and their frequencies seen in children and

adolescents are similar to those described above.

If a side effect has appeared, if one of the side effects

gets worse, or when you suffer from a side effect that

has not been mentioned in the leaflet, you should consult

the doctor.

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://sideeffects.health.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine and any other

medicine must be kept in a closed place out of the

reach and sight of children and/or infants in order

to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by the doctor.

Do not use the medicine after the expiry date (exp.

date) that appears on the carton package. The expiry

date refers to the last day of that month.

Storage conditions: Store refrigerated 2°C-8°C (this

temperature range is predominant in most household

refrigerators). Do not freeze. Store in the original

package.

It is recommended to use immediately after preparing.

The solution can be used within 6 hours, if stored

below 25°C. Carefully dispose of any Enbrel

solution

that was not injected within 6 hours. Do not heat the

medicine!

Before preparing the Enbrel

for injection, the

preparation can be stored outside of the refrigerator,

at a temperature up to a maximum of 25°C for a single

period of up to 4 weeks (no later than the expiry

date). Do not refrigerate again after this time. If the

preparation was not used within 4 weeks of taking it

out of the refrigerator, discard it and do not use it.

It is advisable to write down the date on which

you started to store the preparation outside of the

refrigerator, and the date after which you should no

longer use the preparation (no later than 4 weeks from

the date you took it out of the refrigerator).

Check the solution before use. The solution should be

clear, colorless to slightly yellowish without particles

or crystals. Do not use a cloudy solution or a solution

that contains particles.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine

also contains:

Mannitol (E421), Sucrose, Trometamol.

The syringe contains:

1 ml sterile water for injection

What does the medicine look like and what is the

content of the package

Each package contains:

4 vials with white powder that contains the active

ingredient, etanercept 25 mg

4 pre-filled solvent syringes that contain sterile water

for injection

4 needles

4 vial adapters

8 alcohol swabs

License holder and address: Pfizer Pharmaceuticals

Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725.

Manufacturer and address: Wyeth Pharmaceuticals

Limited, Hampshire, UK

or Pfizer Manufacturing Belgium NV, Puurs, Belgium

Registration number of the medicine in the National Drug

Registry of the Ministry of Health: 11912 30000 06

INSTRUCTIONS FOR PREPARINg AND INjECTINg –

ENBREL

®

POWDER AND SOLVENT FOR PREPARINg

A SOLUTION FOR SUBCUTANEOUS INjECTION

Introduction:

The instructions below explain how to prepare and

inject Enbrel

®

.

Please read the instructions carefully and perform the

steps in the order in which they are presented.

Your doctor or nurse will teach you the self-injection

technique or how to inject your child.

Do not try to prepare or inject Enbrel

to yourself or your

child before you are sure you understood how to mix and

inject the dose.

Do not mix this injection in the same syringe or the same

vial with other medicines.

Setting up for the injection

Wash your hands thoroughly.

Select a clean, well-lit, flat working surface.

The tray should contain all the items listed below (if not,

do not use this tray and consult your pharmacist). Only

use these items, do not use a different syringe.

1 vial containing the medicine Enbrel

1 syringe containing the solvent (water for injection)

1 needle

1 vial adapter

2 alcohol swabs

Check the expiry dates on both the label of the vial

and the syringe. Do not use them after the expiry date,

indicated as a month and year.

Preparing Enbrel

®

for injection

Remove the contents from the tray.

Remove the plastic cap from the Enbrel

vial (see

Diagram 1). Do not remove the gray stopper or the

aluminum ring around the top of the vial.

Diagram 1

Use a new alcohol swab to clean the gray stopper on

the vial. After cleaning, do not touch the stopper with

your hands.

Place the Enbrel

vial upright on a clean, flat surface,

such as a table.

Remove the paper that covers the vial adapter.

While the adapter is still in its plastic wrapping, place

the vial adapter on the tip of the vial (see Diagram 2).

Hold the vial with one hand on the flat surface. Using

the other hand, press down firmly on the package

of the vial adapter, until you feel that the pin of the

vial adapter has penetrated the cap of the vial (see

Diagram 3). Do not press down at an angle (see Diagram

4). It is very important that the pin of the vial adapter will

fully cover the cap of the vial.

While still holding the vial with one hand, remove the

plastic cover from the vial adapter (see Diagram 5).

Diagram 5

Remove the white protective cover from the tip of the

syringe. To remove the white cover from the tip of the

syringe, “break” the perforated region of the cover and

take if off the syringe by bending it up and down until it

breaks off (see Diagram 6). Do not remove the white

“ring” that remains on the syringe.

Diagram 6

Do not use the syringe if the cover was broken to begin

with. Start over with a new tray.

While holding the glass container of the syringe (and

not the white ring) with one hand and the vial adapter

(not the vial) with the other hand, attach the syringe to

the vial adapter on the vial, by inserting the tip of the

syringe into the opening and by turning clockwise until

completely secured (see Diagram 7).

Diagram 7

Adding the solvent

While holding the vial upright on a flat surface, press

the plunger very slowly into the syringe until all of the

solvent in the syringe is in the vial. In this manner, you will

prevent formation of foam (many bubbles) (see Diagram

When all of the solvent is transferred from the syringe to

the Enbrel

vial, the plunger may go back up on its own,

due to air pressure. This should not be of concern.

Diagram 8

Leave the syringe in its place. Gently move the vial a

few times in circular motions, until the powder dissolves

(see Diagram 9). Do not shake the vial. Wait until all the

powder dissolves (usually less than 10 minutes). The

solution should be clear and colorless, with no lumps,

flakes, or particles. Some foam may remain in the vial

– this is normal.

Do not use Enbrel

if all the powder in the vial is not

dissolved within 10 minutes. Start over with a new

tray.

Diagram 9

Withdrawing the Enbrel

®

solution from the vial

With the needle still inserted in the vial, hold the vial

upside down at eye level. Fully push the plunger into

the syringe (see Diagram 10).

Diagram 10

The format of this leaflet was determined by the Ministry of

Health and its content was checked and approved by the

Ministry of Health in January 2015 and updated according

to the guidelines of the Ministry of Health in May 2019.

PATIENT PACKAgE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REgULATIONS

(PREPARATIONS) – 1986

The medicine is dispensed with

a doctor’s prescription only.

Enbrel

®

Powder and solvent for solution for

subcutaneous

injection

Composition:

Each vial with powder contains:

Etanercept 25 mg

Inactive ingredients and allergens - see “Further Information”

section in the leaflet.

Read this leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor

or the pharmacist

This medicine has been prescribed for the treatment of your

ailment. Do not pass it on to others. It may harm them even

if it seems to you that their ailment is similar.

1. WHAT IS THE MEDICINE INTENDED FOR?

Enbrel

is intended to treat rheumatoid arthritis in adults,

juvenile idiopathic arthritis in children and adolescents from

two years of age, psoriatic arthritis in adolescents above

12 years of age and adults, for inflammatory diseases

of the vertebrae of the spinal cord: severe ankylosing

spondylitis in adults and severe non radiographic axial

spondyloarthritis in adults and to treat moderate to severe

plaque psoriasis in adults and severe plaque psoriasis in

children and adolescents from the age of six.

Therapeutic group: TNF antagonist and selective

suppressor of the immune system.

2. BEFORE USINg THE MEDICINE

Do not use the medicine if:

x You/the child are sensitive (allergic) to the active

ingredient etanercept or to any of the other ingredients

contained in the medicine.

You/the child experience an allergic reaction such as

chest tightness, wheezing, dizziness or rash; do not

continue injecting Enbrel

, and refer to the doctor

immediately.

x You/the child have or are at risk of a serious blood

infection called sepsis.

x You/the child have an infection of any kind.

Special warnings regarding use of the medicine:

Women of child-bearing age: use contraception during

the course of treatment with Enbrel

®

and during the

three weeks following completion of treatment with

Enbrel

®

. See additional information in the “Pregnancy

and breastfeeding” subsection.

Refer to the doctor immediately if you/the child

experience an allergic reaction such as chest tightness,

wheezing, dizziness or rash. In such a case, do not inject

more Enbrel

Tell the doctor if you/the child develop a new infection, or

are due to undergo surgery during the course of treatment

with Enbrel

. The doctor may want to monitor you/the

child during the treatment with Enbrel

Tell the doctor if you/the child have a history of recurrent

infections, or if you/the child suffer from diabetes or another

condition that may increase the risk of infection.

Refer to the doctor immediately if you/the child recently

traveled abroad and you/the child develop symptoms of

an infection such as fever, chills or cough. The doctor

may decide to continue to monitor the infection after

completion of treatment with Enbrel

Before commencing treatment with Enbrel

®

, the doctor

will check for symptoms and signs of tuberculosis since

cases of tuberculosis have been reported in patients

taking Enbrel

. The evaluation for tuberculosis may

include a detailed medical history, a chest X-ray and a

Mantoux test.

Tell the doctor if you/the child are suffering or have

suffered from tuberculosis or if you or the child were in

contact with someone who has or had tuberculosis.

Refer to the doctor immediately if you develop

symptoms of tuberculosis (such as persistent cough,

weight loss, tiredness, mild fever), or symptoms of any

other infection during or after completion of treatment

with Enbrel

Refer to the doctor immediately if symptoms such as

persistent fever, sore throat, tendency to bruise under the

skin, bleeding or paleness occur. These symptoms may

indicate a life-threatening blood disturbance that requires

termination of treatment with Enbrel

Tell the doctor if you/the child have hepatitis B or if you/

the child had hepatitis B in the past.

Before commencing treatment with Enbrel

®

,

doctor

will

check

presence

hepatitis B.

Treatment with Enbrel

may result in reactivation of the

disease in patients previously infected with the hepatitis B

virus. If the disease recurs, stop treatment with Enbrel

Tell the doctor if you/the child suffer from hepatitis C.

The doctor may monitor the treatment with Enbrel

case the infection worsens.

Tell the doctor if you/the child suffer from multiple

sclerosis, inflammation of the optic nerve or inflammation

of the spinal cord, so he will be able to determine if

treatment with Enbrel

is appropriate for you.

Tell the doctor if you/the child have a history of

congestive heart failure, as caution must be exercised

in such a case.

Tell your doctor if you/the child are exposed to

chickenpox during the course of treatment with Enbrel

The doctor will determine if there is a need for prophylactic

treatment.

Tell the doctor if you/the child have a history of

alcohol addiction. Do not use Enbrel

to treat alcoholic

hepatitis.

Tell the doctor if you/the child are suffering from

Wegener’s granulomatosis, an inflammation of the blood

vessels, since Enbrel

is not recommended for treatment

of this rare disease.

Tell the doctor if you/the child suffer from diabetes and/

or are taking medicines to treat diabetes. The doctor will

consider whether there is a need to adjust the dosages of

the medicines for diabetes during the course of treatment

with Enbrel

Before commencing treatment with Enbrel

®

, tell the

doctor if you/the child have cancer (e.g., lymphoma) or

if you have a history of cancer. Enbrel

may increase the

risk of having cancer.

Patients suffering from severe rheumatoid arthritis for

a long time may be at increased risk of developing

lymphoma.

Children and adults treated with Enbrel

may have

an increased risk of developing lymphoma or another

cancer.

Some children and adolescents who were treated with

Enbrel

or any other medicine that works in a similar way

as Enbrel

developed cancer, including unusual types,

which sometimes resulted in death.

There have been some reports in which patients receiving

Enbrel

developed different types of skin cancer. Therefore,

you should be closely monitored by the attending doctor

and have periodic skin tests performed. Refer to the

doctor immediately if you notice any changes in your/

the child’s skin.

Children and adolescents:

It is recommended that children be vaccinated before

commencing treatment with Enbrel

. Tell the doctor if

you/the child are due to receive any vaccines. Do not

give certain vaccines (such as oral polio vaccine) during

the course of treatment with Enbrel

Tell the doctor if the child suffers from abdominal cramps

and pain, diarrhea, weight loss or blood in the stools.

Cases of inflammatory bowel disease have been reported

among children with idiopathic arthritis under treatment

with Enbrel

If you/the child are taking, or have recently taken,

other medicines, including non-prescription medicines

and nutritional supplements, tell the doctor or the

pharmacist. Especially inform the doctor or pharmacist

if you/the child are taking:

Sulfasalazine intended for the treatment of inflammatory

bowel diseases and rheumatoid arthritis.

Abatacept intended for the treatment of rheumatoid

arthritis.

Anakinra intended for the treatment of rheumatoid

arthritis.

Do not use preparations containing the active ingredients

anakinra or abatacept during the course of treatment

with Enbrel

Use of the medicine and food and beverage

Enbrel

can be used without regard to food and

beverages.

Pregnancy and breastfeeding

Enbrel

should only be used during pregnancy if clearly

needed.

Women of child-bearing age must use contraception during

the course of treatment with Enbrel

and for three weeks

after completing the treatment.

You should consult your doctor if you are pregnant, think

you may be pregnant, or are planning to have a baby.

If Enbrel

was used during pregnancy, the baby may

have a higher risk of getting an infection. In addition,

one study found more birth defects when the mother

had received Enbrel

during pregnancy, compared with

mothers who had not received Enbrel

or similar medicines

(TNF antagonists), but there was no report of a particular

kind of birth defect.

Another study found no increased risk of birth defects when

the mother had received Enbrel

in pregnancy. Your doctor

will help you to decide whether the benefits of treatment

outweigh the potential risk to your baby.

Before vaccinating the baby, it is important to inform the

doctor and the medical staff treating the baby that Enbrel

was used during pregnancy (further information is provided

in the “Special warnings regarding use of the medicine –

children and adolescents” subsection).

Do not breastfeed during the treatment with Enbrel

, since

Enbrel

passes into breast milk.

Driving and use of machinery

Enbrel

is not expected to affect the ability to drive or use

machines.

3. HOW SHOULD YOU USE THE MEDICINE?

Enbrel

is administered as a subcutaneous injection after

being prepared. Do not swallow.

Always use the preparation according to the doctor’s

instructions. Check with the doctor or pharmacist if you

are uncertain regarding the dosage and treatment regimen

of the preparation.

The dosage and treatment regimen will be determined by

the doctor only.

The doctor will determine the duration of treatment and if

there is a need for further treatment, in accordance with

the response.

If no improvement is seen after 12 weeks of treatment with

Enbrel

, the doctor may decide to stop the treatment.

The doctor will show you how to prepare and measure

the correct dose.

Do not exceed the recommended dose.

Then, slowly pull back the plunger to draw the liquid

into the syringe (see Diagram 11). For adult patients,

draw up the entire volume of liquid. For children, only

draw up the volume the doctor has prescribed. After

removing Enbrel

from the vial, some air may remain in

the syringe. Do not worry; you will remove the air in a

later step.

Diagram 11

With the vial still upside down, release the syringe from

the vial adapter that is on the vial, by turning counter-

clockwise (see Diagram 12).

Diagram 12

Place the filled syringe on a clean and flat surface.

Be careful not to push the plunger of the syringe

downward.

(Note: after completing these steps, a small amount of

liquid may remain in the vial. This is normal).

Attaching the needle to the syringe

The needle is provided in a plastic package that keeps

it sterile.

To open the plastic container, hold the short and wide

end in one hand and with the other hand, hold the long

part of the plastic container.

To break the seal, bend the long end up and down until

is snaps off (see Diagram 13).

Diagram 13

When the seal has been broken off, remove the short,

wide end of the plastic container.

The needle remains in the long part of the package.

While holding the container and the needle in one hand,

pick up the syringe and insert the tip of the syringe into

the opening of the needle.

Attach the syringe to the needle by turning clockwise,

until it is completely closed (see Diagram 14).

Diagram 14

Carefully remove the needle cover by steadily pulling

it straight off of the syringe. Take care not to touch the

needle and not to allow the needle to touch any other

surface (see Diagram 15). Take care not to bend or

distort the cover while removing it to prevent

damaging the needle.

Diagram 15

Hold the syringe upright and expel the air bubbles by

slowly pushing the plunger until all air is expelled (see

Diagram 16).

Diagram 16

Choosing an injection site

The three recommended injection sites for Enbrel

are:

(A) the front of the middle thighs; (B) the abdomen,

except for the 5 cm area right around the navel; (C) the

outer area of the upper arms (see Diagram 17). If you

are injecting Enbrel

to yourself, do not choose the outer

area of the upper arms as an injection site.

Diagram 17

A different site should be used for each new dose. Make

sure that the dose is injected at least 3 cm from the

previous injection site. Do not inject into areas where

the skin is tender, bruised, red, or hard. Avoid injecting

the dose into areas with scars or stretch marks (keep

notes on the location of the previous injections).

If you or your child have psoriasis, do not try to inject

directly into an affected area, such as raised, thick, red,

or cracked skin (psoriasis skin lesions).

Preparing the injection site and injecting Enbrel

®

Wipe the injection site with an alcohol swab, using

a circular motion. Do not touch this area after the

disinfection and before giving the injection.

When the injection site has dried, pinch and hold it with

one hand. With the other hand, hold the syringe like a

pencil.

With a quick and short motion, push the needle into

the skin at an angle between 45° and 90° (see Diagram

18). With experience, you will find the angle that is most

comfortable for you or your child. Be careful not to push

the needle into the skin too slowly, or too forcefully.

Diagram 18

When the needle is completely inserted into the skin,

release the skin that you are holding. With your free

hand, hold the syringe near its base to stabilize it. Now,

push the plunger to inject all of the solution at a slow,

steady rate (see Diagram 19).

Diagram 19

When the syringe is empty, remove the needle from the

skin, being careful to keep it at the same angle it was

when it was inserted. There may be slight bleeding at

the injection site. You can press a cotton ball or a gauze

over the injection site for 10 seconds. Do not rub the

injection site. A bandage can be used, if necessary.

Disposing of the equipment

Do not reuse a syringe and needle.

Dispose of the needle and syringe in accordance with the

instructions given by the doctor, nurse or pharmacist.

All questions will be addressed by a doctor, nurse or

pharmacist familiar with the medicine.

syringe

vial

needle

vial adapter

2 alcohol swabs

Diagram 2

Diagram 4

INCORRECT!

Diagram 3

CORRECT!

Enbrel PFS and PFP, LPD, CC

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2014-0007256, 2019-0052786

1. NAME OF THE MEDICINAL PRODUCT

Enbrel 25 mg Pre-filled Syringe

Enbrel 50 mg solution for injection in pre-filled syringe or pre-filled pen.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled syringe

of Enbrel 25 mg solution for injection - contains 25 mg of

etanercept.

Each pre-filled syringe of Enbrel 50 mg solution for injection - contains 50 mg of

etanercept.

Each pre-filled pen of

Enbrel 50 mg solution for injection -

contains 50 mg of etanercept.

Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by

recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression

system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the

extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75)

to the Fc domain of human IgG1. This Fc component contains the hinge, CH

and CH

regions, but not the CH

region of IgG1. Etanercept contains 934 amino acids and has an

apparent molecular weight of approximately 150 kilodaltons. The specific activity of

etanercept is 1.7 x 10

units/mg.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection.

The solution is clear, and colourless or pale yellow.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Rheumatoid arthritis

Enbrel is indicated for the treatment of active

rhematoid

arthritis in adults when the response

to disease-modifying antirheumatic drugs

(DMARDs)

including methotrexate (unless

contraindicated

has been inadequate.

Enbrel can be

used in combination with methotrexate

patients who do not respond

adequately

to methotrexate

alone.

Reducing signs and symptoms and inhibiting the progression of structural damage in

patients

with

moderately to severely

active rheumatoid arthritis

Enbrel, alone or in combination with methotrexate, has been shown to reduce the rate of

progression of joint damage as measured by X-ray and to improve physical function.

Enbrel PFS and PFP, LPD, CC

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Juvenile idiopathic arthritis

Treatment of polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis

in children and adolescents from the age of 2 years who have had an inadequate response to,

or who have proved intolerant of, methotrexate.

Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an

inadequate response to, or who have proved intolerant of, methotrexate.

Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had

an inadequate response to, or who have proved intolerant of, conventional therapy.

Enbrel has not been studied in children aged less than 2 years.

Psoriatic arthritis

Treatment of active and progressive psoriatic arthritis in adults when the response to previous

disease-modifying antirheumatic drug therapy has been inadequate. Enbrel has been shown to

improve physical function in patients with psoriatic arthritis, and to reduce the rate of

progression of peripheral

joint damage as measured by X-ray in patients with polyarticular

symmetrical subtypes of the disease.

Axial spondyloarthritis

Ankylosing spondylitis (AS)

Treatment of adults with severe active ankylosing spondylitis who have had an inadequate

response to conventional therapy.

Non-radiographic axial spondyloarthritis

Treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs

of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance

imaging (MRI) evidence, who have had an inadequate response to nonsteroidal anti-

inflammatory drugs (NSAIDs).

Plaque psoriasis

Treatment of adults

patients (18 years or older)

with moderate to severe plaque psoriasis

who are

candidates for

systemic therapy

or phototherapy.

Paediatric plaque psoriasis

Treatment of chronic severe plaque psoriasis in children and adolescents from the age of

6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or

phototherapies.

4.2

Posology and method of administration

Enbrel treatment should be initiated and supervised by specialist physicians experienced in

the diagnosis and treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic

arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis or

paediatric plaque psoriasis.

Enbrel pre filled syringe is available in strengths of 25 and 50 mg.

The Enbrel pre-filled pen is available in a 50 mg strength.

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Posology

Rheumatoid arthritis

25 mg Enbrel administered twice weekly is the recommended dose. Alternatively, 50 mg

administered once weekly has been shown to be safe and effective (see section 5.1).

Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis

The recommended dose is 25 mg Enbrel administered twice weekly, or 50 mg administered

once weekly.

For all of the above indications, available data suggest that a clinical response is usually

achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in

a patient not responding within this time period.

Plaque psoriasis

The recommended dose of Enbrel is 25 mg administered twice weekly or 50 mg administered

once weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks

followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once weekly. Treatment

with Enbrel should continue until remission is achieved, for up to 24 weeks. Continuous

therapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1).

Treatment should be discontinued in patients who show no response after 12 weeks. If re-

treatment with Enbrel is indicated, the same guidance on treatment duration should be

followed. The dose should be 25 mg twice weekly or 50 mg once weekly.

Special populations

Renal and hepatic impairment

No dose adjustment is required.

Elderly

No dose adjustment is required. Posology and administration are the same as for adults 18-64

years of age.

Paediatric population

The dosage of Enbrel is based on body weight for paediatric patients. Patients weighing less

than 62.5 kg should be accurately dosed on a mg/kg basis using Enbrel 25 mg powder and

solvent for solution for injection presentation (see below for dosing for specific indications).

Patients weighing 62.5 kg or more, may be dosed using a fixed-dose pre-filled syringe or pre-

filled pen.

Juvenile idiopathic arthritis

The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg per dose), given twice

weekly as a subcutaneous injection with an interval of 3-4 days between doses or 0.8 mg/kg

(up to a maximum of 50 mg per dose) given once weekly. Discontinuation of treatment

should be considered in patients who show no response after 4 months.

No formal clinical trials have been conducted in children aged 2 to 3 years. However, limited

safety data from a patient registry suggest that the safety profile in children from 2 to 3 years

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of age is similar to that seen in adults and children aged 4 years and older, when dosed every

week with 0.8 mg/kg subcutaneously (see section 5.1).

There is generally no applicable use of Enbrel in children aged below 2 years in the indication

juvenile idiopathic arthritis.

Paediatric plaque psoriasis (age 6 years and above)

The recommended dose is 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for

up to 24 weeks. Treatment should be discontinued in patients who show no response after 12

weeks.

If re-treatment with Enbrel is indicated, the above guidance on treatment duration should be

followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

There is generally no applicable use of Enbrel in children aged below 6 years in the indication

plaque psoriasis.

Method of administration

Enbrel is administered by subcutaneous injection (see section 6.6).

Comprehensive instructions for administration are given in this leaflet, section 7

4.3

Contraindications

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

Sepsis or risk of sepsis.

Treatment with Enbrel should not be initiated in patients with active infections, including

chronic or localised infections.

4.4

Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trademark and the

batch number of the administered product should be clearly recorded (or stated) in the patient

file.

Infections

Patients should be evaluated for infections before, during, and after treatment with Enbrel,

taking into consideration that the mean elimination half-life of etanercept is approximately

70 hours (range 7 to 300 hours).

Serious infections, sepsis, tuberculosis, and opportunistic infections, including invasive fungal

infections, listeriosis and legionellosis, have been reported with the use of Enbrel (see section

4.8). These infections were due to bacteria, mycobacteria, fungi, viruses and parasites

(including protozoa). In some cases, particular fungal and other opportunistic infections have

not been recognised, resulting in delay of appropriate treatment and sometimes death. In

evaluating patients for infections, the patient’s risk for relevant opportunistic infections (e.g.,

exposure to endemic mycoses) should be considered.

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Patients who develop a new infection while undergoing treatment with Enbrel should be

monitored closely. Administration of Enbrel should be discontinued if a patient develops a

serious infection. The safety and efficacy of Enbrel in patients with chronic infections have

not been evaluated. Physicians should exercise caution when considering the use of Enbrel in

patients with a history of recurring or chronic infections or with underlying conditions that

may predispose patients to infections, such as advanced or poorly controlled diabetes.

Tuberculosis

Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with extra-

pulmonary location, have been reported in patients treated with Enbrel.

Before starting treatment with Enbrel, all patients must be evaluated for both active and

inactive (‘latent’) tuberculosis. This evaluation should include a detailed medical history with

personal history of tuberculosis or possible previous contact with tuberculosis and previous

and/or current immunosuppressive therapy. Appropriate screening tests, i.e., tuberculin skin

test and chest X-ray, should be performed in all patients (local recommendations may apply).

It is recommended that the conduct of these tests should be recorded. Prescribers are

reminded of the risk of false negative tuberculin skin test results, especially in patients who

are severely ill or immunocompromised.

If active tuberculosis is diagnosed, Enbrel therapy must not be initiated. If inactive (‘latent’)

tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-

tuberculosis therapy before the initiation of Enbrel, and in accordance with local

recommendations. In this situation, the benefit/risk balance of Enbrel therapy should be very

carefully considered.

All patients should be informed to seek medical advice if signs/symptoms suggestive of

tuberculosis (e.g., persistent cough, wasting/weight loss, low-grade fever) appear during or

after Enbrel treatment.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus

(HBV) and had received concomitant TNF-antagonists, including Enbrel, has been reported.

This

includes reports of reactivation of hepatitis B in patients who were anti-HBc positive but

HBsAg negative. Patients should be tested for HBV infection before initiating treatment with

Enbrel. For patients who test positive for HBV infection, consultation with a physician with

expertise in the treatment of hepatitis B is recommended. Caution should be exercised when

administering Enbrel in patients previously infected with HBV. These patients should be

monitored for signs and symptoms of active HBV infection throughout therapy and for

several weeks following termination of therapy. Adequate data from treating patients infected

with

HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are not

available. In patients who develop HBV infection, Enbrel should be stopped and effective

anti-viral therapy with appropriate supportive treatment should be initiated.

Worsening of hepatitis C

There have been reports of worsening of hepatitis C in patients receiving Enbrel. Enbrel

should be used with caution in patients with a history of hepatitis C.

Concurrent treatment with anakinra

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Concurrent administration of Enbrel and anakinra has been associated with an increased risk

of serious infections and neutropenia compared to Enbrel alone. This combination has not

demonstrated increased clinical benefit. Thus, the combined use of Enbrel and anakinra is not

recommended (see sections 4.5 and 4.8).

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased

incidences of serious adverse events. This combination has not demonstrated increased

clinical benefit; such use is not recommended (see section 4.5).

Allergic reactions

The needle cover of the pre-filled syringe and the needle cap of the pre-filled pen contains

latex (dry natural rubber) that may cause hypersensitivity reactions when handled by, or when

Enbrel is administered to, persons with known or possible latex sensitivity.

Allergic reactions associated with Enbrel administration have been reported commonly.

Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If

any serious allergic or anaphylactic reaction occurs, Enbrel therapy should be discontinued

immediately and appropriate therapy initiated.

Immunosuppression

The possibility exists for TNF-antagonists, including Enbrel, to affect host defences against

infections and malignancies since TNF mediates inflammation and modulates cellular

immune responses. In a study of 49 adult patients with rheumatoid arthritis treated with

Enbrel, there was no evidence of depression of delayed-type hypersensitivity, depression of

immunoglobulin levels, or change in enumeration of effector cell populations.

Two juvenile idiopathic arthritis patients developed varicella infection and signs and

symptoms of aseptic meningitis, which resolved without sequelae. Patients with a significant

exposure to varicella virus should temporarily discontinue Enbrel therapy and be considered

for prophylactic treatment with Varicella Zoster Immune Globulin.

The safety and efficacy of Enbrel in patients with immunosuppression have not been

evaluated.

Malignancies and lymphoproliferative disorders

Solid and haematopoietic malignancies (excluding skin cancers)

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have

been received in the postmarketing period (see section 4.8).

In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have

been observed among patients receiving a TNF-antagonist compared with control patients.

However, the occurrence was rare, and the follow-up period of placebo patients was shorter

than for patients receiving TNF-antagonist therapy. In the postmarketing setting, cases of

leukaemia have been reported in patients treated with TNF-antagonists. There is an increased

background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-

standing, highly active, inflammatory disease, which complicates risk estimation.

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Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or

other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot

be excluded. Caution should be exercised when considering TNF-antagonist therapy for

patients with a history of malignancy or when considering continuing treatment in patients

who develop a malignancy.

Malignancies, some fatal, have been reported among children, adolescents and young adults

(up to 22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age),

including Enbrel, in the postmarketing setting. Approximately half the cases were

lymphomas. The other cases represented a variety of different malignancies and included rare

malignancies typically associated with immunosuppression. A risk for the development of

malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.

Skin cancers

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated

with TNF-antagonists, including Enbrel. Postmarketing cases of Merkel cell carcinoma have

been reported very infrequently in patients treated with Enbrel. Periodic skin examination is

recommended for all patients, particularly those with risk factors for skin cancer.

Combining the results of controlled clinical trials, more cases of NMSC were observed in

patients receiving Enbrel compared with control patients, particularly in patients with

psoriasis.

Vaccinations

Live vaccines should not be given concurrently with Enbrel. No data are available on the

secondary transmission of infection by live vaccines in patients receiving Enbrel. In a

double-blind, placebo-controlled, randomised clinical study in adult patients with psoriatic

arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at

week 4. In this study, most psoriatic arthritis patients receiving Enbrel were able to mount

effective B-cell immune response to pneumococcal polysaccharide vaccine, but titres in

aggregate were moderately lower, and few patients had two-fold rises in titres compared to

patients not receiving Enbrel. The clinical significance of this is unknown.

Autoantibody formation

Treatment with Enbrel may result in the formation of autoimmune antibodies (see section

4.8).

Haematologic reactions

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome,

have been reported in patients treated with Enbrel. Caution should be exercised in patients

being treated with Enbrel who have a previous history of blood dyscrasias. All patients and

parents/caregivers should be advised that if the patient develops signs and symptoms

suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising,

bleeding, paleness) whilst on Enbrel, they should seek immediate medical advice. Such

patients should be investigated urgently, including full blood count; if blood dyscrasias are

confirmed, Enbrel should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with Enbrel

(see section 4.8). Additionally, there have been rare reports of peripheral demyelinating

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polyneuropathies (including Guillain-Barré syndrome, chronic inflammatory demyelinating

polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although

no clinical trials have been performed evaluating Enbrel therapy in patients with multiple

sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have

shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic

assessment, is recommended when prescribing Enbrel to patients with pre-existing or recent

onset of demyelinating disease, or to those who are considered to have an increased risk of

developing demyelinating disease.

Combination therapy

In a controlled clinical trial of two years duration in rheumatoid arthritis patients, the

combination of Enbrel and methotrexate did not result in unexpected safety findings, and the

safety profile of Enbrel when given in combination with methotrexate was similar to the

profiles reported in studies of Enbrel and methotrexate alone. Long-term studies to assess the

safety of the combination are ongoing. The long-term safety of Enbrel in combination with

other disease-modifying antirheumatic drugs (DMARD) has not been established.

The use of Enbrel in combination with other systemic therapies or phototherapy for the

treatment of psoriasis has not been studied.

Renal and hepatic impairment

Based on pharmacokinetic data (see section 5.2), no dose adjustment is needed in patients

with renal or hepatic impairment; clinical experience in such patients is limited.

Congestive heart failure (Cardiac failure congestive)

Physicians should use caution when using Enbrel in patients who have congestive heart

failure (CHF). There have been postmarketing reports of worsening of CHF, with and without

identifiable precipitating factors, in patients taking Enbrel. There have also been rare (< 0.1%)

reports of new onset CHF, including CHF in patients without known pre-existing

cardiovascular disease. Some of these patients have been under 50 years of age. Two large

clinical trials evaluating the use of Enbrel in the treatment of CHF were terminated early due

to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible

tendency toward worsening CHF in those patients assigned to Enbrel treatment.

Alcoholic hepatitis

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with

Enbrel or placebo for moderate to severe alcoholic hepatitis, Enbrel was not efficacious, and

the mortality rate in patients treated with Enbrel was significantly higher after 6 months.

Consequently, Enbrel should not be used in patients for the treatment of alcoholic hepatitis.

Physicians should use caution when using Enbrel in patients who also have moderate to

severe alcoholic hepatitis.

Wegener's granulomatosis

A placebo-controlled trial, in which 89 adult patients were treated with Enbrel in addition to

standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a

median duration of 25 months, has not shown Enbrel to be an effective treatment for

Wegener’s granulomatosis. The incidence of non-cutaneous malignancies of various types

was significantly higher in patients treated with Enbrel than in the control group. Enbrel is not

recommended for the treatment of Wegener’s granulomatosis.

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Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of Enbrel in patients receiving

medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these

patients.

Special populations

Elderly

In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis,

no overall differences in adverse events, serious adverse events, and serious infections in

patients age 65 or older who received Enbrel were observed compared with younger patients.

However, caution should be exercised when treating the elderly and particular attention paid

with respect to occurrence of infections.

Paediatric population

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all

immunisations in agreement with current immunisation guidelines prior to initiating Enbrel

therapy (see Vaccinations, above).

Inflammatory bowel disease (IBD) and uveitis

in patients with juvenile idiopathic arthritis

(JIA)

There have been reports of IBD and uveitis in JIA patients being treated with Enbrel (see

section 4.8).

4.5

Interaction with other medicinal products and other forms of interaction

Concurrent treatment with anakinra

Adult patients treated with Enbrel and anakinra were observed to have a higher rate of serious

infection when compared with patients treated with either Enbrel or anakinra alone (historical

data).

In addition, in a double-blind, placebo-controlled trial in adult patients receiving background

methotrexate, patients treated with Enbrel and anakinra were observed to have a higher rate of

serious infections (7%) and neutropenia than patients treated with Enbrel (see sections 4.4 and

4.8). The combination Enbrel and anakinra has not demonstrated increased clinical benefit,

and is therefore not recommended.

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased

incidences of serious adverse events. This combination has not demonstrated increased

clinical benefit; such use is not recommended (see section 4.4).

Concurrent treatment with sulfasalazine

In a clinical study of adult patients who were receiving established doses of sulfasalazine, to

which Enbrel was added, patients in the combination group experienced a statistically

significant decrease in mean white blood cell counts in comparison to groups treated with

Enbrel or sulfasalazine alone. The clinical significance of this interaction is unknown.

Physicians should use caution when considering combination therapy with sulfasalazine.

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Non-interactions

In clinical trials, no interactions have been observed when Enbrel was administered with

glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs

(NSAIDs), analgesics, or methotrexate. See section 4.4 for vaccination advice.

No clinically significant pharmacokinetic drug-drug interactions were observed in studies

with methotrexate, digoxin or warfarin.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should consider the use of appropriate contraception to

avoid becoming pregnant during Enbrel therapy and for three weeks after discontinuation of

therapy.

Pregnancy

Developmental toxicity studies performed in rats and rabbits have revealed no evidence of

harm to the foetus or neonatal rat due to etanercept. The effects of etanercept on pregnancy

outcomes have been investigated in two observational cohort studies. A higher rate of major

birth defects was observed in one observational study comparing pregnancies exposed to

etanercept (n=370) during the first trimester with pregnancies not exposed to etanercept or

other TNF-antagonists (n=164) (adjusted odds ratio 2.4, 95% CI: 1.0-5.5). The types of major

birth defects were consistent with those most commonly reported in the general population

and no particular pattern of abnormalities was identified. No change in the rate of

spontaneous abortion, stillbirth, or minor malformations was observed. In another

observational multi-country registry study comparing the risk of adverse pregnancy outcomes

in women exposed to etanercept during the first 90 days of pregnancy (n=425) to those

exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth

defects (crude odds ratio [OR]= 1.22, 95% CI: 0.79-1.90; adjusted OR = 0.96, 95% CI: 0.58-

1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early

pregnancy). This study also showed no increased risks of minor birth defects, preterm birth,

stillbirth, or infections in the first year of life for infants born to women exposed to etanercept

during pregnancy. Enbrel should only be used during pregnancy if clearly needed.

Etanercept crosses the placenta and has been detected in the serum of infants born to female

patients treated with Enbrel during pregnancy. The clinical impact of this is unknown,

however, infants may be at increased risk of infection. Administration of live vaccines to

infants for 16 weeks after the mother’s last dose of Enbrel is generally not recommended.

Breast-feeding

Etanercept has been reported to be excreted in human milk following subcutaneous

administration. In lactating rats following subcutaneous administration, etanercept was

excreted in the milk and detected in the serum of pups. Because immunoglobulins, in

common with many medicinal products, can be excreted in human milk, a decision must be

made whether to discontinue breast-feeding or to discontinue Enbrel therapy, taking into

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

Fertility