Metex 50 mg/ml Injektionslösung, Fertigspritze Injektionslösung in einer Fertigspritze

Deutschland - Deutsch - BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte)

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Gebrauchsinformation PIL
Fachinformation SPC
Wirkstoff:
Methotrexat-Dinatrium
Verfügbar ab:
Medac Gesellschaft für klinische Spezialpräparate m.b.H.
ATC-Code:
L01BA01
INN (Internationale Bezeichnung):
Methotrexate disodium
Darreichungsform:
Injektionslösung in einer Fertigspritze
Zusammensetzung:
Methotrexat-Dinatrium 54.84mg
Berechtigungsstatus:
gültig
Zulassungsnummer:
70930.00.00

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Packungsbeilage Packungsbeilage - Englisch

Package leaflet: Information for the user

Metoject 50 mg/ml solution for injection, pre-filled syringe

methotrexate

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

information for you.

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

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

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

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

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

not listed in this leaflet. See section 4.

What is in this leaflet

What Metoject is and what it is used for

What you need to know before you use Metoject

How to use Metoject

Possible side effects

How to store Metoject

Contents of the pack and other information

1.

What Metoject is and what it is used for

Metoject contains methotrexate as active substance.

Methotrexate is a substance with the following properties:

it interferes with the growth of certain cells in the body that reproduce quickly

it reduces the activity of the immune system (the body’s own defence mechanism)

it has anti-inflammatory effects

Metoject is indicated for the treatment of

active rheumatoid arthritis in adult patients.

polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal

anti-inflammatory drugs (NSAIDs) has been inadequate.

severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy

such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients.

mild to moderate Crohn’s disease in adult patients when adequate treatment with other medicines is

not possible.

Rheumatoid arthritis (RA)

is a chronic collagen disease, characterised by inflammation of the synovial

membranes (joint membranes). These membranes produce a fluid which acts as a lubricant for many

joints. The inflammation causes thickening of the membrane and swelling of the joint.

Juvenile arthritis concerns children and adolescents less than 16 years. Polyarthritic forms are indicated if

5 or more joints are affected within the first 6 months of the disease.

Psoriatic arthritis is a kind of arthritis with psoriatic lesions of the skin and nails, especially at the joints of

fingers and toes.

Psoriasis is a common chronic skin disease, characterised by red patches covered by thick, dry, silvery,

adherent scales.

Metoject modifies and slows down the progression of the disease.

Crohn’s disease is a type of inflammatory bowel disease that may affect any part of the gastrointestinal

tract causing symptoms such as abdominal pain, diarrhoea, vomiting or weight loss.

2.

What you need to know before you use Metoject

Do not use Metoject:

if you are allergic to methotrexate or any of the other ingredients of this medicine (listed in

section 6),

if you suffer from severe liver or kidney diseases or blood diseases,

if you regularly drink large amounts of alcohol,

if you suffer from a severe infection, e.g. tuberculosis, HIV or other immunodeficiency syndromes,

if you suffer from ulcers in the mouth, stomach ulcer or intestinal ulcer,

if you are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and fertility”),

if you receive vaccinations with live vaccines at the same time.

Warnings and precautions

Talk to your doctor or pharmacist before using Metoject if:

you are elderly or if you feel generally unwell and weak,

your liver function is impaired,

you suffer from dehydration (water loss).

Special precautionary measures for treatment with Metoject

Methotrexate temporarily affects sperm and egg production, which is reversible in most cases.

Methotrexate can cause miscarriage and severe birth defects. You must avoid becoming pregnant when

using methotrexate and for at least six months after treatment has stopped. See also section “Pregnancy,

breast-feeding and fertility”.

Recommended follow-up examinations and safety measures

Even when Metoject is administered in low doses, severe side effects can occur. In order to detect them in

time, check-ups and laboratory tests have to be carried out by your doctor.

Before therapy

Before starting the treatment, blood samples will be taken in order to check that you have enough blood

cells, and tests will be carried out to check your liver function, serum albumin (a protein in the blood) and

kidney function. Your doctor will also check if you suffer from tuberculosis (infectious disease in

combination with little nodules in the affected tissue) and a chest X-ray will be taken.

During therapy

You will have the following tests at least once a month during the first six months and at least every three

months thereafter:

Examination of the mouth and throat for alterations of the mucosa

Blood tests

Check of liver function

Check of kidney function

Check of respiratory system and if necessary lung function test

Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with

methotrexate. If you experience symptoms of spitting or coughing up blood you should contact your

doctor immediately.

Methotrexate may affect your immune system and vaccination results. It may also affect the result of

immunological tests. Inactive, chronic infections (e.g. herpes zoster [shingles], tuberculosis, hepatitis B

or C) may flare up. During therapy with Metoject you must not be vaccinated with live vaccines.

Radiation-induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction).

Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

Enlarged lymph nodes (lymphoma) may occur and therapy must then be stopped.

Diarrhoea can be a toxic effect of Metoject and requires an interruption of therapy. If you suffer from

diarrhoea please speak to your doctor.

Certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients

receiving methotrexate. Such side effects cannot be excluded when methotrexate is used to treat other

diseases.

Other medicines and Metoject

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

Please note that this also applies to medicines that you will take in the future.

The effect of the treatment may be affected if Metoject is administered at the same time as certain other

medicines:

Antibiotics

such as: tetracyclines, chloramphenicol, and non-absorbable broad-spectrum

antibiotics, penicillines, glycopeptides, sulphonamides, ciprofloxacin and cefalotin (medicines to

prevent/fight certain infections).

Non-steroidal anti-inflammatory

drugs or

salicylates

(medicines against pain and/or

inflammation such as acetylsalicylic acid, diclofenac and ibuprofen or pyrazole).

Probenecid

(medicine against gout).

Weak organic acids like loop

diuretics

(“water tablets”).

Medicines, which may have adverse effects on the

bone marrow

, e.g. trimethoprim-

sulphamethoxazole (an antibiotic) and pyrimethamine.

Other

medicines used to treat rheumatoid arthritis

such as leflunomide, sulfasalazine and

azathioprine.

Mercaptopurine (a

cytostatic

medicine).

Retinoids (medicine against

psoriasis

and other dermatological diseases).

Theophylline (medicine against

bronchial asthma

and other lung diseases).

Some medicines against

stomach trouble

such as omeprazole and pantoprazole.

Hypoglycaemics (medicines that are used to

lower the blood sugar

Vitamins containing

folic acid

may impair the effect of your treatment and should only be taken when

advised by your doctor.

Vaccination with live vaccine must be avoided.

Metoject with food, drink and alcohol

Alcohol as well as large amounts of coffee, caffeine-containing soft drinks and black tea should be

avoided during treatment with Metoject.

Pregnancy, breast-feeding and fertility

Pregnancy

Do not use Metoject during pregnancy or if you are trying to become pregnant. Methotrexate can cause

birth defects, harm the unborn child or cause miscarriage. It is associated with malformations of the skull,

face, heart and blood vessels, brain and limbs. Therefore, it is very important that methotrexate is not

given to pregnant patients or patients planning to become pregnant.

In women of child-bearing age, any

possibility of pregnancy must be excluded with appropriate measures, e.g. pregnancy test before starting treatment.

You must avoid becoming pregnant whilst taking methotrexate and for at least 6 months after treatment is

stopped by using reliable contraception throughout this time (see also section “Warnings and

precautions”).

If you do become pregnant during treatment or suspect you might be pregnant, speak to your doctor as

soon as possible. You should be offered advice regarding the risk of harmful effects on the child through

treatment.

If you wish to become pregnant you should consult your doctor, who may refer you for specialist advice

before the planned start of treatment.

Breast-feeding

Stop breast-feeding prior to and during treatment with Metoject.

Male fertility

The available evidence does not indicate an increased risk of malformations or miscarriage if the father

takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded. Methotrexate

may be genotoxic. This means that the medicine may cause genetic mutation. Methotrexate can affect

sperm production with the potential to cause birth defects. Therefore, you should avoid fathering a child

or to donate semen whilst taking methotrexate and for at least 6 months after treatment is stopped.

Driving and using machines

Treatment with Metoject may cause adverse reactions affecting the central nervous system, e.g. tiredness

and dizziness. Thus the ability to drive a vehicle and/or to operate machines may, in certain cases, be

compromised. If you feel tired or drowsy you should not drive or use machines.

Metoject contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-

free”.

3.

How to use Metoject

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

you are not sure.

Your doctor decides on the dose, which is adjusted individually. Usually it takes 4 – 8 weeks before there

is any effect of the treatment.

Metoject is administered by or under the supervision of a physician or healthcare staff as an injection

once a week only

. Together with your doctor you decide on a suitable weekday each week on which you

receive your injection. Metoject may be injected intramuscularly (in a muscle), intravenously (in a vein)

or subcutaneously (under the skin).

Use in children and adolescents

As there is very little data about giving the medicine intravenously in children and adolescents, it must

only be injected under the skin or into a muscle.

The doctor decides on the appropriate dose in children and adolescents with polyarthritic forms of

juvenile idiopathic arthritis.

Metoject is not recommended in children less than 3 years of age due to insufficient experience in this age

group.

Method and duration of administration

Metoject is injected

once weekly!

The duration of the treatment is determined by the treating physician. Treatment of rheumatoid arthritis,

juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis and Crohn’s disease with Metoject is a

long-term treatment.

At the start of your therapy, Metoject may be injected by medical staff. In certain cases your doctor may

decide to instruct you how to inject Metoject under the skin yourself. You will then receive appropriate

training.

Under no circumstances should you try to inject Metoject yourself before you have received such

training.

Please refer to the instructions for use at the end of the leaflet.

The manner of handling and disposal must be consistent with that of other cytostatic preparations in

accordance with local requirements. Pregnant healthcare personnel should not handle and/or administer

Metoject.

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of

contamination, the affected area must be rinsed immediately with plenty of water.

If you use more Metoject than you should

If you use more Metoject than you should, talk to your doctor immediately.

If you forget to use Metoject

Do not take a double dose to make up for a forgotten dose.

If you stop using Metoject

If you stop using Metoject, talk to your doctor immediately.

If you have the impression that the effect of Metoject is too strong or too weak, you should talk to your

doctor or pharmacist.

4.

Possible side effects

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

The frequency as well as the degree of severity of the side effects depends on the dosage level and the

frequency of administration. As severe side effects may occur even at low dosage, it is important that you

are monitored regularly by your doctor. Your doctor will do

tests to check for abnormalities

developing

in the blood (such as low white blood cells, low platelets, and lymphoma) and changes in the kidneys and

the liver.

Tell your doctor immediately

if you experience any of the following symptoms, as these may indicate a

serious, potentially life-threatening side effect, which require urgent specific treatment:

persistent dry, non-productive cough, shortness of breath and fever

; these may be signs of an

inflammation of the lungs [common]

spitting or coughing blood;

these might be signs of bleeding from the lungs [not known]

symptoms of liver damage such as yellowing of the skin and whites of the eyes;

methotrexate

can cause chronic liver damage (liver cirrhosis), formation of scar tissue in the liver (liver

fibrosis), fatty degeneration of the liver [all uncommon], inflammation of the liver (acute

hepatitis) [rare] and liver failure [very rare]

allergy symptoms such as skin rash including red itchy skin, swelling of the hands, feet,

ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing)

and feeling you are going to faint;

these may be signs of severe allergic reactions or an

anaphylactic shock [rare]

symptoms of kidney damage such as swelling of the hands, ankles or feet or changes in

frequency of urination or decrease (oliguria) or absence of urine (anuria);

these may be signs

of kidney failure [rare]

symptoms of infections, e.g. fever, chills, achiness, sore throat;

methotrexate can make you

more susceptible to infections. Severe infections like a certain type of pneumonia (

Pneumocystis

carinii pneumonia

) or blood poisoning (sepsis) may occur [rare]

symptoms such as weakness of one side of the body (stroke) or pain, swelling, redness and

unusual warmth in one of your legs (deep vein thrombosis); This may happen when a

dislodged blood clot causes a blockage of a blood vessel

(thromboembolic event) [rare]

fever and serious deterioration of your general condition, or sudden fever accompanied by a

sore throat or mouth, or urinary problems

; methotrexate can cause a sharp fall in certain white

blood cells (agranulocytosis) and severe bone marrow suppression [very rare]

unexpected bleeding, e.g. bleeding gums, blood in the urine, vomiting blood or bruising,

these can be signs of a severely reduced number of blood platelets caused by severe courses of

bone marrow depression [very rare]

symptoms such as severe headache often in combination with fever, neck stiffness, feeling

sick, vomiting, disorientation and sensitivity to light

may indicate an inflammation of the

membranes of the brain (acute aseptic meningitis) [very rare]

certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer

patients receiving methotrexate. Such side effects cannot be excluded when methotrexate therapy

is used to treat other diseases. Signs of this kind of brain disorders may be

altered mental state,

movement disorders (ataxia), visual disturbances or disturbances of memory

[not known]

severe skin rash or blistering of the skin (this can also affect your mouth, eyes and genitals)

these may be signs of conditions called Stevens Johnson syndrome or burned skin syndrome

(toxic epidermal necrolysis/Lyell’s syndrome) [very rare]

In the following, please find the other side effects that may occur:

Very common:

may affect more than 1 in 10 people

Inflammation of the mouth lining, indigestion, feeling sick, loss of appetite, abdominal pain.

Abnormal liver function test (ASAT, ALAT, bilirubin, alkaline phosphatase).

Common:

may affect up to 1 in 10 people

Mouth ulcers, diarrhoea.

Rash, reddening of the skin, itching.

Headache, tiredness, drowsiness.

Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets.

Uncommon:

may affect up to 1 in 100 people

Throat inflammation.

Inflammation of the bowels, vomiting, inflammation of pancreas, black or tarry stools,

gastrointestinal ulcers and bleeding.

Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, skin ulcers,

shingles, inflammation of blood vessels, herpes-like skin rash, hives.

Onset of diabetes mellitus.

Dizziness, confusion, depression.

Decrease in serum albumin.

Decrease in the number of all blood cells and platelets.

Inflammation and ulcer of the urinary bladder or vagina, reduced kidney function, disturbed

urination.

Joint pain, muscle pain, reduction of bone mass.

Rare:

may affect up to 1 in 1,000 people

Inflammation of gum tissue

Increased skin pigmentation, acne, blue spots on the skin due to vessel bleeding

(ecchymosis, petechiae), allergic inflammation of blood vessels.

Decreased number of anti-bodies in the blood.

Infection (incl. reactivation of inactive chronic infection), red eyes (conjunctivitis).

Mood swings (mood alterations).

Visual disturbances.

Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart,

obstruction of cardiac filling due to fluid in the sac around the heart.

Low blood pressure.

Formation of scar tissue in the lung (pulmonary fibrosis), shortness of breath and bronchial asthma,

accumulation of fluid in the sac around the lung

Stress fracture.

Electrolyte disturbances.

Fever, wound-healing impairment.

Very rare:

may affect up to 1 in 10,000 people

Acute toxic dilatation of the gut (toxic megacolon).

Increased pigmentation of the nails, inflammation of the cuticles (acute paronychia), deep infection

of hair follicles (furunculosis), visible enlargement of small blood vessels.

Local damage (formation of sterile abscess, changes in the fatty tissue) of injection site following

administration into a muscle or under the skin.

Pain, loss of strength or sensation of numbness or tingling in arms and legs, changes in taste

(metallic taste), convulsions, paralysis, meningism.

Impaired vision, non-inflammatory eye disorder (retinopathy).

Loss of sexual drive, impotence, male breast enlargement, defective sperm formation

(oligospermia), menstrual disorder, vaginal discharge.

Enlargement of lymphatic nodes (lymphoma).

Lymphoproliferative disorders (excessive growth of white blood cells).

Not known:

frequency cannot be estimated from the available data

Increased number of certain white blood cells.

Nosebleed.

Proteins in urine.

Feeling of weakness.

Bone damage in the jaw (secondary to excessive growth of white blood cells).

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or

damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur

commonly. Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin

reactions were observed, decreasing during therapy.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via (see details below). By reporting side

effects you can help provide more information on the safety of this medicine.

[To be completed nationally]

5.

How to store Metoject

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

Store below 25 °C.

Keep the pre-filled syringes in the outer carton in order to protect from light.

Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last

day of that month.

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.

Contents of the pack and other information

What Metoject contains

The active substance is methotrexate. 1 ml of solution contains methotrexate disodium

corresponding to 50 mg methotrexate.

The other ingredients are sodium chloride, sodium hydroxide, water for injections.

What Metoject looks like and contents of the pack

Metoject pre-filled syringes contain a clear, yellow-brown solution.

<For packs containing syringes with safety system only>The syringe is equipped with a safety system to

prevent needle stick injury and reuse of the needle.

The following pack sizes are available:

Pre-filled syringes with embedded sc. injection needles, graduation and alcohol pads containing 0.15 ml,

0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 0.55 ml and 0.60 ml solution for injection

in packs of 1, 4, 5, 6, 10, 11, 12, and 24 pre-filled syringes with safety system.

Pre-filled syringes with enclosed sc. injection needles, graduation and alcohol pads containing 0.15 ml,

0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 0.55 ml and 0.60 ml solution for injection

in packs of 1, 4, 5, 6, 10, 11, 12, and 24 pre-filled syringes.

For i.m and i.v use, a needle suitable for these routes of administration must be used: The needle enclosed

in the pack is suitable for s.c. use only.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

Tel: +49 4103 8006 0

Fax: +49 4103 8006 100

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria, Belgium, Bulgaria, Czech Republic, Finland, Greece, Hungary, Iceland, Netherlands, Romania,

Slovak Republic, Slovenia, Spain, Sweden, United Kingdom: Metoject

Demark, Estonia, Latvia, Lithuania, Norway, Poland and Portugal: Metex

Germany: metex

Italy: Reumaflex

This leaflet was last revised in 2018-10-05

<For packs containing syringes without safety system only>

Instructions for use

Carefully read the instructions below before starting your injection, and always use the injection

technique advised by your doctor, pharmacist or nurse.

For any problem or question, contact your doctor, pharmacist or nurse.

Preparation

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

Collect necessary items before you begin:

1 Metoject pre-filled syringe

1 alcohol pad (provided in the packaging)

Wash your hands carefully. Before use, check the Metoject syringe for visual defects (or cracks).

Injection site

The best sites for injection are:

- upper thighs,

- abdomen except around the navel.

If someone is helping you with the injection, he/she may also

give the injection into the back of your arms, just below the

shoulder.

Change the injection site with each injection. This may reduce

the risk of developing irritations at the injection site.

Never inject into skin that is tender, bruised, red, hard, scarred or

where you have stretch marks. If you have psoriasis, you should

try not to inject directly into any raised, thick, red or scaly skin

patches or lesions.

Injecting the solution

Unpack the methotrexate pre-filled syringe and read the package leaflet carefully. Remove

the pre-filled syringe from the packaging at room temperature.

Disinfection

Choose an injection site and disinfect it with a swab soaked in

disinfectant.

Allow at least 60 seconds for the disinfectant to dry.

Remove the protective plastic cap

Carefully remove the grey protective plastic

cap by pulling it straight off the syringe. If

the cap is very stiff, turn it slightly with a

pulling movement.

Important:

Do not

touch the needle of the

pre-filled syringe!

Inserting the cannula

Using two fingers, pinch up a fold of skin and quickly

insert the needle into the skin at a 90-degree angle.

Injection

Insert the needle fully into the fold of skin. Push the

plunger down slowly and inject the liquid underneath

your skin. Hold the skin securely until the injection is

completed.

Carefully pull the needle straight out.

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of

contamination, the affected area must be rinsed immediately with plenty of water.

If you or someone around you is injured by the needle, consult your doctor immediately and do not

use this pre-filled syringe.

Disposal and other handling

The manner of handling and throwing away of the medicine and pre-filled syringe must be in

accordance with local requirements. Pregnant healthcare personnel should not handle and/or

administer Metoject.

<For packs containing syringes with safety system only>

Instructions for use

Carefully read the instructions below before starting your injection, and always use the injection

technique advised by your doctor, pharmacist or nurse.

For any problem or question, contact your doctor, pharmacist or nurse.

Preparation

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

Collect necessary items before you begin:

1 Metoject pre-filled syringe with safety system

1 alcohol pad (provided in the packaging)

Wash your hands carefully. Before use, check the Metoject syringe for visual defects (or cracks).

Injection site

The best sites for injection are:

- upper thighs,

- abdomen except around the navel.

If someone is helping you with the injection, he/she may also give

the injection into the back of your arms, just below the shoulder.

Change the injection site with each injection. This may reduce the

risk of developing irritations at the injection site.

Never inject into skin that is tender, bruised, red, hard, scarred or

where you have stretch marks. If you have psoriasis, you should try

not to inject directly into any raised, thick, red or scaly skin patches

or lesions.

Injecting the solution

Unpack the methotrexate pre-filled syringe with safety system and read the package leaflet

carefully. Remove the pre-filled syringe from the packaging at room temperature.

Disinfection

Choose an injection site and disinfect it with a swab soaked in disinfectant.

Allow at least 60 seconds for the disinfectant to dry.

Remove the protective plastic cap

Carefully remove the grey protective plastic cap

by pulling it straight off the syringe. If the cap is

very stiff, turn it slightly with a pulling

movement.

Important:

Do not

touch the needle of the pre-

filled syringe!

Inserting the cannula

Using two fingers, pinch up a fold of skin and quickly

insert the needle into the skin at a 90-degree angle.

Injection

Insert the needle fully into the fold of skin. Push the

plunger down slowly and inject the liquid underneath

your skin

Removing the needle

Hold the skin securely until the injection is

completed. Carefully pull the needle straight

out.

A protective cover will automatically enclose the

needle.

Note: The protection system that is triggered by the release of the protective cover can only be activated

when the syringe has been emptied completely by pushing down the plunger as far as it goes.

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of

contamination, the affected area must be rinsed immediately with plenty of water.

If you or someone around you is injured by the needle, consult your doctor immediately and do

not use this pre-filled syringe.

Disposal and other handling

The manner of handling and throwing away of the medicine and pre-filled syringe must be in

accordance with local requirements. Pregnant healthcare personnel should not handle and/or

administer Metoject.

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Metoject 50 mg/ml solution for injection, pre-filled syringe

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 50 mg methotrexate (as methotrexate disodium).

1 pre-filled syringe of 0.15 ml contains 7.5 mg methotrexate.

1 pre-filled syringe of 0.20 ml contains 10 mg methotrexate.

1 pre-filled syringe of 0.25 ml contains 12.5 mg methotrexate.

1 pre-filled syringe of 0.30 ml contains 15 mg methotrexate.

1 pre-filled syringe of 0.35 ml contains 17.5 mg methotrexate.

1 pre-filled syringe of 0.40 ml contains 20 mg methotrexate.

1 pre-filled syringe of 0.45 ml contains 22.5 mg methotrexate.

1 pre-filled syringe of 0.50 ml contains 25 mg methotrexate.

1 pre-filled syringe of 0.55 ml contains 27.5 mg methotrexate.

1 pre-filled syringe of 0.60 ml contains 30 mg methotrexate

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection, pre-filled syringe.

Clear, yellow-brown solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Metoject is indicated for the treatment of

active rheumatoid arthritis in adult patients,

polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal

anti-inflammatory drugs (NSAIDs) has been inadequate,

severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy

such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients,

mild to moderate Crohn’s disease either alone or in combination with corticosteroids in adult patients

refractory or intolerant to thiopurines.

4.2

Posology and method of administration

Metoject should only be prescribed by physicians who are familiar with the various characteristics of the

medicinal product and its mode of action. The administration should routinely be done by health

professionals. If the clinical situation permits the treating physician can, in selected cases, delegate the

subcutaneous administration to the patient her/himself. In these cases, detailed administration instructions

from the physician are obligate. Metoject is injected

once weekly

The patient is to be explicitly informed about the fact of administration

once weekly

. It is advisable to

determine a fixed, appropriate weekday as day of injection.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions).

Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some

cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).

Dosage in adult patients with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate

once weekly

, administered either

subcutaneously, intramuscularly or intravenously. Depending on the individual activity of the disease and

tolerability by the patient, the initial dose may be increased gradually by 2.5 mg per week. A weekly dose

of 25 mg should in general not be exceeded. However, doses exceeding 20 mg/week are associated with

significant increase in toxicity, especially bone marrow suppression

.

Response to treatment can be

expected after approximately 4 – 8 weeks. Upon achieving the therapeutically desired result, the dose

should be reduced gradually to the lowest possible effective maintenance dose.

Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic

arthritis

The recommended dose is 10 – 15 mg/m² body surface area (BSA)/

once weekly

. In therapy-refractory

cases the weekly dosage may be increased up to 20 mg/m² body surface area/

once weekly

. However, an

increased monitoring frequency is indicated if the dose is increased.

Due to limited data availability about intravenous use in children and adolescents, parenteral

administration is limited to subcutaneous and intramuscular injection.

Patients with JIA should always be referred to a rheumatology specialist

in the treatment of

children/adolescents.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is

available for this population (see section 4.4).

Dosage in patients with psoriasis vulgaris and psoriatic arthritis

It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to

therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate

once weekly

, administered either subcutaneously, intramuscularly or intravenously. The dose is to be

increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses

exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow

suppression. Response to treatment can generally be expected after approximately 2 – 6 weeks. Upon

achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible

effective maintenance dose.

Dosage in patients with Crohn’s disease

Induction treatment:

25 mg/week administered either subcutaneously, intravenously or intramuscularly.

Response to treatment can be expected after approximately 8 to 12 weeks.

Maintenance treatment:

15 mg/week administered either subcutaneously, intravenously or intramuscularly.

There is not sufficient experience in the paediatric population to recommend Metoject for the treatment of

Crohn’s disease in this population.

Maximum weekly dose

The dose should be increased as necessary but should in general not exceed the maximum recommended

weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should

not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Patients with renal impairment

Metoject should be used with caution in patients with impaired renal function. The dose should be

adjusted as follows:

Creatinine clearance (ml/min)

Dose

100 %

30 – 59

50 %

< 30

Metoject must not be used

See section 4.3.

Patients with hepatic impairment

Methotrexate should be administered with great caution, if at all, to patients with significant current or

previous liver disease, especially if due to alcohol. If bilirubin is

>

5 mg/dl (85.5 µmol/l), methotrexate is

contraindicated.

For the full list of contraindications, see section 4.3.

Use in elderly patients

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well

as lower folate reserves which occur with increased age.

Use in patient with a third distribution space (pleural effusions, ascitis)

As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a

third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration

may be required (see section 5.2 and 4.4).

Method of administration

The medicinal product is for single use only.

Metoject can be given by intramuscular, intravenous or subcutaneous route (in children and adolescents

only subcutaneous or intramuscular).

The overall duration of the treatment is decided by the physician.

Note:

If changing the oral application to parenteral administration a reduction of the dose may be required due

to the variable bioavailability of methotrexate after oral administration.

Folic acid supplementation may be considered according to current treatment guidelines.

4.3

Contraindications

Metoject is contraindicated in the case of

hypersensitivity to the active substance or to any of the excipients listed in section 6.1,

severe liver impairment (see section 4.2),

alcohol abuse,

severe renal impairment (creatinine clearance less than 30 ml/min., see section 4.2 and section 4.4),

pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or

significant anaemia,

serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,

ulcers of the oral cavity and known active gastrointestinal ulcer disease,

pregnancy and breast-feeding (see section 4.6),

concurrent vaccination with live vaccines.

4.4

Special warnings and precautions for use

Patients must be clearly informed that the therapy has to be administered

once a week

, not every day.

Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic

effects or adverse reactions may be detected and evaluated with minimal delay. Therefore, methotrexate

should be only administered by, or under the supervision of physicians whose knowledge and experience

includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic

reactions, the patient should be fully informed by the physician of the risks involved and the

recommended safety measures.

Recommended examinations and safety measures

Before beginning or reinstituting methotrexate therapy after a rest period

Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum

albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy (at least once a month during the first six months and every three months thereafter)

An increased monitoring frequency should be considered also when the dose is increased.

Examination of the mouth and throat for mucosal changes

Complete blood count with differential blood count and platelets. Haemopoietic suppression caused

by methotrexate may occur abruptly and with apparently safe doses. Any profound drop in white-

cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate

supportive therapy. Patients should be advised to report all signs and symptoms suggestive of

infection. Patients taking simultaneous administration of haematotoxic medicinal products (e.g.

leflunomide) should be monitored closely with blood count and platelets.

Liver function tests: Particular attention should be given to the appearance of liver toxicity.

Treatment should not be instituted or should be discontinued if any abnormality of liver function

tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to

normal within two weeks after which treatment may be recommenced at the discretion of the

physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in

rheumatological indications.

For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. Further

research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen

can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and

differentiate between patients with no risk factors and patients with risk factors such as excessive

prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family

history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to

hepatotoxic drugs or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g

or more.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three

times of the upper limit of normal have been reported by patients at a frequency of 13 – 20 %. In the

case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of

therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not

be taken during treatment with methotrexate

unless clearly necessary

and the consumption of alcohol

should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be

exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide).

The same should be taken into account with the simultaneous administration of haematotoxic

medicinal products (e.g. leflunomide).

Renal function should be monitored by renal function tests and urinalysis (see sections 4.2 and 4.3).

As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be

expected in the case of renal impairment, which may result in severe undesirable effects.

Where renal function may be compromised (e.g. in the elderly), monitoring should take place more

frequently. This applies in particular when medicinal products are administered concomitantly that

affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal anti-inflammatory

medicinal products) or that can potentially lead to impairment of blood formation. Dehydration may

also intensify the toxicity of methotrexate.

Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if

necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of

methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific

pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous

lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial

pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported.

Although clinically variable, the typical patient with methotrexate-induced lung disease presents

with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be

excluded. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate

therapy. This lesion can occur at all doses.

In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in

rheumatologic and related indications. This event may also be associated with vasculitis and other

comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage

is suspected to confirm the diagnosis.

Methotrexate may, due to its effect on the immune system, impair the response to vaccination

results and affect the result of immunological tests. Particular caution is also needed in the presence

of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of

eventual activation. Vaccination using live vaccines must not be carried out under methotrexate

therapy.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must

be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation

of cytotoxic therapy.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been

reported to cause an acute megaloblastic pancytopenia in rare instances.

Radiation-induced dermatitis and sunburn can reappear under methotrexate therapy (recall-reaction).

Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions).

Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some

cases, discontinuation of methotrexate administration. Pleural effusions and ascites should be drained

prior to initiation of methotrexate treatment (see section 5.2).

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise

haemorrhagic enteritis and death from intestinal perforation may occur.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease

the effectiveness of methotrexate.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis

which is not adequately responsive to other forms of therapy, but only when the diagnosis has been

established by biopsy and/or after dermatological consultation.

Encephalopathy/leukoencephalopathy have been reported in oncologic patients receiving methotrexate

therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.

Fertility and reproduction

Fertility

Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in

humans, during and for a short period after cessation of therapy, and to cause impaired fertility, affecting

spermatogenesis and oogenesis during the period of its administration

effects that appear to be

reversible on discontinuing therapy.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks

of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female

patients of childbearing potential (see section 4.6). The absence of pregnancy must be confirmed before

Metoject is used. If women of a sexually mature age are treated, effective contraception must be

performed during treatment and for at least six months after.

For contraception advice for men see section 4.6.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially

“sodium-free”.

Paediatric population

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are

available for this population (see section 4.2).

4.5

Interaction with other medicinal products and other forms of interaction

Nitrous oxide

The use of nitrous oxide potentiates the effect of methotrexate on folate, yielding increased toxicity such

as severe unpredictable myelosuppression and stomatitis. Whilst this effect can be reduced by

administering calcium folinate, the concomitant use should be avoided.

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products

The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol

consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4).

Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be

monitored with special care. The same should be taken into account with the simultaneous administration

of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine). The

incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with

methotrexate.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of

hepatotoxicity.

Oral antibiotics

Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can

interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the

bacterial metabolism.

Antibiotics

Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual

cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate

with simultaneous haematological and gastro-intestinal toxicity may occur.

Medicinal products with high plasma protein binding

Methotrexate is plasma protein bound and may be displaced by other protein bound medicinal products

such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines,

chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to

increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory agents

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the

elimination of methotrexate and higher serum concentrations may be assumed inducing higher

haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate and

nonsteroidal anti-inflammatory medicinal products or salicylates are combined.

Medicinal products with adverse reactions on the bone marrow

In the case of medication with medicinal products which may have adverse reactions on the bone marrow

(e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention

should be paid to the possibility of pronounced impairment of blood formation.

Medicinal products which cause folate deficiency

The concomitant administration of products which cause folate deficiency (e.g. sulphonamides,

trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore

advisable in the presence of existing folic acid deficiency.

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease

the effectiveness of methotrexate.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when Metoject is

administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds,

penicillamine, hydroxychloroquine, sulfasalazine, azathioprin, cyclosporin).

Sulfasalazine

Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of

methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through

sulfasalazine, such undesirable effects have only been observed in rare individual cases in the course of

several studies.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and

mercaptopurine may therefore require dose adjustment.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to

interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal

elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the

metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when

used concurrently with methotrexate.

Caffeine- or theophylline-containing beverages

An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing

soft drinks, black tea) should be avoided during methotrexate therapy.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used

during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating

therapy, women of childbearing potential must be informed of the risk of malformations associated with

methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures,

e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after

any gap of contraception). Female patients of reproductive potential must be counselled regarding

pregnancy prevention and planning.

Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in

animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded.

Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following

paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient

data to estimate the risks of malformations or miscarriage following paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended to use

reliable contraception during treatment of the male patient and for at least 6 months after cessation of

methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of

methotrexate.

Pregnancy

Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3). If

pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice

should be given regarding the risk of harmful effects on the child associated with treatment and

ultrasonography examinations should be performed to confirm normal foetal development.

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see

section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause

foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central

nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine

growth restriction and congenital malformations in case of exposure during pregnancy.

Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose

methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched

patients treated with drugs other than methotrexate.

Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate

treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in

disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but

higher rates of spontaneous abortions and congenital malformations are expected.

When methotrexate was discontinued prior to conception, normal pregnancies have been reported.

Breast-feeding

Methotrexate is excreted in human milk. Because of the potential for serious adverse reactions in breast-

fed infants, Metoject is contraindicated during breast-feeding (see section 4.3). Therefore breast-feeding

must be discontinued prior to and throughout administration.

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, methotrexate

has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to

be reversible after discontinuation of therapy in most cases.

4.7

Effects on ability to drive and use machines

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metoject has

minor or moderate influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity,

hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-

Johnson syndrome.

Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal

disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver function

tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently (common) occurring

adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia,

interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema,

erythema and pruritus.

Tabulated list of adverse reactions

The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal

disorders.

The following headings are used to organise the undesirable effects in order of frequency:

Very common (

1/10), common (

1/100 to < 1/10), uncommon (

1/1,000 to < 1/100), rare (

1/10,000

to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)

Infections and infestations

Uncommon: Pharyngitis.

Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis.

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very rare: Lymphoma (see “description” below).

Blood and lymphatic system disorders

Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression, lymphoproliferative disorders

(see “description” below).

Not known: Eosinophilia.

Immune system disorders

Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.

Metabolism and nutrition disorders

Uncommon: Precipitation of diabetes mellitus.

Psychiatric disorders

Uncommon: Depression, confusion.

Rare: Mood alterations.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness.

Very rare: Pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic

taste), convulsions, meningism, acute aseptic meningitis, paralysis.

Not known: Encephalopathy/leukoencephalopathy.

Eye disorders

Rare: Visual disturbances.

Very rare: Impaired vision, retinopathy.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms

indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of

breath and fever.

Rare: Pulmonary fibrosis,

Pneumocystis carinii

pneumonia, shortness of breath and bronchial asthma,

pleural effusion.

Not known: Epistaxis, pulmonary alveolar haemorrhage.

Gastrointestinal disorders

Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain.

Common: Oral ulcers, diarrhoea.

Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis.

Rare: Gingivitis.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Hepatobiliary disorders (see section 4.4)

Very common: Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and

bilirubin).

Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Skin and subcutaneous tissue disorders

Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster,

vasculitis, herpetiform eruptions of the skin, urticaria.

Rare: Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased

pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

Musculoskeletal and connective tissue disorders

Uncommon: Arthralgia, myalgia, osteoporosis.

Rare: Stress fracture.

Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders).

Renal and urinary disorders

Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare: Renal failure, oliguria, anuria, electrolyte disturbances.

Not known: Proteinuria.

Reproductive system and breast disorders

Uncommon: Inflammation and ulceration of the vagina.

Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal

discharge.

General disorders and administration site conditions

Rare: Fever, wound-healing impairment.

Very rare: Local damage (formation of sterile abscess, lipodystrophy) of injection site following

intramuscular or subcutaneous administration.

Not known: Asthenia.

Description of selected adverse reactions

The appearance and degree of severity of undesirable effects depends on the dose level and the frequency

of administration. However, as severe undesirable effects can occur even at lower doses, it is

indispensable that patients are monitored regularly by the doctor at short intervals.

Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and

other lymphoproliferative disorders which subsided in a number of cases once treatment with

methotrexate had been discontinued.

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or

damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur

commonly.

Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin

reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain)

were observed, decreasing during therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via (see details below).

[To be completed nationally]

4.9

Overdose

Symptoms of overdose

Toxicity of methotrexate mainly affects the haematopoietic system.

Treatment measures in the case of overdose

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of

methotrexate should be administered intravenously or intramuscularly within one hour and dosing

continued until the serum levels of methotrexate are below 10

mol/l.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation

of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis

has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been

reported with acute, intermittent haemodialysis using a high flux dialyser.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Folic acid analogues, ATC code: L01BA01

Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and

polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for

the treatment of Crohn’s disease.

Mechanism of action

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as

antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus

inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the

management of psoriasis, psoriasis arthritis, chronic polyarthritis and Crohn’s disease, is due to an anti-

inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in

extracellular adenosine concentration at inflamed sites contributes to these effects.

International clinical guidelines reflect the use of methotrexate as a second choice for Crohn’s disease

patients that are intolerant or have failed to respond to first-line immunomodulating agents as

azathioprine (AZA) or 6-mercaptopurine (6-MP).

The adverse events observed in the studies performed with methotrexate for Crohn’s disease at

cumulative doses have not shown a different safety profile of methotrexate than the profile it is already

known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of

Crohn’s disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4

and 4.6).

5.2

Pharmacokinetic properties

Absorption

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-

dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean

bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are

possible (25 – 100 %). Maximum serum concentrations are achieved after 1 – 2 hours.

Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.

Distribution

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body

tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in

particular, which can be retained for weeks or months. When administered in small doses, methotrexate

passes into the cerebrospinal fluid in minimal amounts. The terminal half-life is on average 6 – 7 hours

and demonstrates considerable variation (3 – 17 hours). The half-life can be prolonged to 4 times the

normal length in patients who possess a third distribution space (pleural effusion, ascites).

Biotransformation

Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle

metabolite is 7-hydroxymethotrexate.

Elimination

Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active

secretion in the proximal tubulus.

Approx. 5 – 20 % methotrexate and 1 – 5 % 7-hydroxymethotrexate are eliminated biliary. There is

pronounced enterohepatic circulation.

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to

hepatic impairment is not known.

5.3

Preclinical safety data

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic.

Methotrexate is mutagenic

in vivo

in vitro

. As conventional carcinogenicity studies have not been

performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered

not classifiable

as to its carcinogenicity to humans.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Sodium hydroxide for pH adjustment

Water for injections

6.2

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal

products.

6.3

Shelf-life

2 years.

6.4

Special precautions for storage

Store below 25 °C. Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5

Nature and contents of container

Nature of container

Pre-filled syringes of colourless glass (type I) of 1 ml capacity with embedded injection needle. Plunger

stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form the syringe

plunger

Pre-filled syringes of colourless glass (type I) of 1 ml capacity with embedded injection needle. Plunger

stoppers of chlorobutyl rubber (type I), polystyrene rods inserted on the stopper to form the syringe

plunger and a safety system to prevent needle stick injury and reuse of the needle.

Pre-filled syringes of colourless glass (type I) of 1 ml capacity with enclosed injection needle. Plunger

stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form the syringe

plunger.

Pack sizes

Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml,

0.55 ml or 0.60 ml solution are available in packs of 1, 4, 5, 6, 10, 11, 12 and 24 syringes with embedded

s.c. injection needle and alcohol pads.

Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml,

0.55 ml or 0.60 ml solution are available in packs of 1, 4, 5, 6, 10, 11, 12 and 24 syringes with embedded

s.c. injection needle with safety system and alcohol pads.

Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml,

0.55 ml or 0.60 ml solution are available in packs of 1, 4, 5, 6, 10, 11, 12 and 24 syringes with enclosed

s.c. injection needle and alcohol pads.

For i.m and i.v use, a needle suitable for these routes of administration must be used: The needle enclosed

in the pack is suitable for s.c. use only.

All pack sizes are available with graduation marks.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in

accordance with local requirements. Pregnant healthcare personnel should not handle and/or administer

Metoject.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the

affected area must be rinsed immediately with ample amount of water.

For single use only.

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

In some regions Metoject may be marketed with a safety system to prevent needle stick injury and reuse

of the needle.

Instructions for subcutaneous use of Metoject without safety system

The best places for the injection are:

- upper thighs,

- abdomen except around the navel.

Clean the area around the chosen injection site (e.g. by using the

enclosed alcohol pad).

Pull the protective plastic cap straight off.

Build a skin fold by gently squeezing the area at the injection site.

The fold must be held pinched until the syringe is removed from the skin after the injection.

Push the needle fully into the skin at a 90-degree angle.

Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from the

skin at the same 90-degree angle.

Instructions for subcutaneous use of Metoject with safety system

The best places for the injection are:

- upper thighs,

- abdomen except around the navel.

Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad).

Pull the protective plastic cap straight off.

Build a skin fold by gently squeezing the area at the injection site.

The fold must be held pinched until the syringe is removed from the skin after the injection.

Push the needle fully into the skin at a 90-degree angle.

Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from the

skin at the same 90-degree angle.

A protective cover will automatically enclose the needle.

Note: The protection system that is triggered by the release of the protective cover can only be activated

when the syringe has been emptied completely by pushing down the plunger as far as it goes.

7.

MARKETING AUTHORISATION HOLDER

medac

Gesellschaft für klinische Spezialpräparate mbH

Theaterstr. 6

22880 Wedel

Germany

8.

MARKETING AUTHORISATION NUMBER

<[To be completed nationally]>

9.

DATE OF FIRST MARKETING AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 02 October 2008

Date of latest renewal: 02 October 2013

10.

DATE OF REVISION OF THE TEXT

2018-10-05

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