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METHOTREXATE 50MG/ML SOLUTION FOR INJECTION

Active substance(s): METHOTREXATE

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Metoject® 50mg/ml solution for injection
(methotrexate)
This product is available using the above name but will be referred to as Metoject
throughout the following leaflet.
Read all of this leaflet carefully before you start using this medicine because it
contains important information for you.

Other medicines and Metoject
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.
The effect of the treatment may be affected if Metoject is administered at the same time as
certain other drugs:



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:
1. What Metoject is and what it is used for
2. What you need to know before you use Metoject
3. How to use Metoject
4. Possible side effects
5. How to store Metoject
6. 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.










Medicines harming the liver or the blood count, e.g. leflunomide
Antibiotics (medicines to prevent/fight certain infections) such as: tetracyclines,
chloramphenicol, and non-absorbable broadspectrum antibiotics, penicillines,
glycopeptides, sulphonamides (sulphur containing medicines that prevent/fight certain
infections), ciprofloxacin and cefalotin
Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or
inflammation)
Probenecid (medicine against gout)
Weak organic acids like loop diuretics (“water tablets”) or some medicines used for
treatment of pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and
ibuprofen) and pyrazole (e.g. metamizol for treating pain)
Medicinal products, which may have adverse effects on the bone marrow, e.g.
trimethoprim-sulphamethoxazole (an antibiotic) and pyrimethamine
Sulphasalazine (antirheumatic medicine)
Azathioprine (an immunosuppressive agent sometimes used in severe forms of
rheumatoid arthritis)
Mercaptopurine (a cytostatic agent)
Retinoids (medicine against psoriasis and other dermatological diseases)
Theophylline (medicine against bronchial asthma and other lung diseases)
Proton-pump inhibitors (medicines against stomach trouble)
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 should 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
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a
baby, ask your doctor or pharmacist for advice before taking this medicine.
You must not take Metoject during pregnancy. There is a risk of harm to the foetus and
miscarriage. Men and women should use an effective method of birth control during
treatment and for a further six months after treatment with Metoject has been discontinued.
In women of child-bearing age, any existing pregnancy must be excluded with certainty by
taking appropriate measures, e.g. pregnancy test, prior to therapy.
As methotrexate can be genotoxic, all women who wish to become pregnant are advised to
consult a genetic counselling centre, if possible, already prior to therapy, and men should
seek advice about the possibility of sperm preservation before starting therapy.
Breast-feeding should be stopped prior to and during treatment with Metoject.

Metoject modifies and slows down the progression of the disease.

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.

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.

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

2. What you need to know before you use Metoject

3. How to 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).
 suffer from severe liver or kidney diseases or blood diseases.
 regularly drink large amounts of alcohol.
 suffer from a severe infection, e.g. tuberculosis, HIV or other immunodeficiency
syndromes.
 suffer from ulcers in the mouth, stomach ulcer or intestinal ulcer.
 are pregnant or breast-feeding.
 receive vaccinations with live vaccines at the same time.

Your doctor decides on the dosage, which is adjusted individually.
Usually it takes 4 – 8 weeks before there is any effect of the treatment.

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

Warnings and precautions
Talk to your doctor or pharmacist before taking Metoject if:
 you are elderly or if you feel generally unwell and weak.
 your liver function is impaired.
 you suffer from dehydration (water loss).
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, tests 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 Xray 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

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.
Encephalopathy (a brain disorder) / leukoencephalopathy (a special disorder of the white
brain substance) have been reported in cancer patients receiving methotrexate therapy and
cannot be excluded for methotrexate therapy in other diseases.

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).
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 longterm 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 health care 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 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, 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 (pneumonia) [common — may affect up to 1 in
10 people]
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
of the liver (liver fibrosis), fatty degeneration of the liver [all uncommon — may affect up
to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare — may affect up to 1
in 1,000 people] and liver failure [very rare — may affect up to 1 in 10,000 people]
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 — may affect up to 1 in 1,000 people]
symptoms of kidney damage such as swelling of the hands, ankles or feet or
changes in frequency of urination or decrease or absence of urine; these may be
signs of kidney failure [rare — may affect up to 1 in 1,000 people]
symptoms of infections, e.g. fever, chills, achiness, sore throat; methotrexate can
make you more susceptible to infections. Rarely [may affect up to 1 in 1,000 people]
severe infections like a certain type of pneumonia (Pneumocystis carinii pneumonia) or
blood poisoning (sepsis) may occur
severe diarrhoea, vomiting blood and black or tarry stools; these symptoms may
indicate a rare [may affect up to 1 in 1,000 people] severe complication of the
gastrointestinal system caused by methotrexate e.g. gastrointestinal ulcers
symptoms associated with the blockage (occlusion) of a blood vessel by a
dislodged blood clot (thromboembolic event) 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); methotrexate can cause thromboembolic events [rare may affect up to 1 in 1,000 people]
fever and serious deterioration of your general condition, or sudden fever
accompanied by a sore throat or mouth, or urinary problems; methotrexate can
very rarely [may affect up to 1 in 10,000 people] cause a sharp fall in white blood cells
(agranulocytosis) and severe bone marrow suppression
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 — may affect up to 1 in
10,000 people]
severe skin rash or blistering of the skin (this can also affect your mouth, eyes
and genitals); these may be signs of the very rare [may affect up to 1 in 10,000 people]
conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal
necrolysis)

In the following, please find the other side effects that may occur:
Very common: may affect more than 1 in 10 people
 Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite
 Increase in liver enzymes
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 (leukopenia, anaemia, thrombocytopenia)
Uncommon: may affect up to 1 in 100 people
 Throat inflammation, inflammation of the bowels, vomiting
 Increased sensitivity to light, loss of hair, increased number of rheumatic nodules,
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 blood cells and platelets
 Inflammation and ulcer of the urinary bladder or vagina, reduced kidney function,
disturbed urination
 Joint pain, muscle pain, osteoporosis (reduction of bone mass)
Rare: may affect up to 1 in 1,000 people
 Increased skin pigmentation, acne, blue spots due to vessel bleeding
 Allergic inflammation of blood vessels, fever, red eyes, infection, wound-healing
impairment, decreased number of anti-bodies in the blood
 Visual disturbances
 Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart
 Low blood pressure
 Lung fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the sac
around the lung
 Electrolyte disturbances
Very rare: may affect up to 1 in 10,000 people
 Profuse bleeding, toxic megacolon (acute toxic dilatation of the gut)
 Increased pigmentation of the nails, inflammation of the cuticles, furunculosis (deep
infection of hair follicles), 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
 Impaired vision, pain, loss of strength or sensation of numbness or tingling in arms and
legs, changes in taste (metallic taste), convulsions, paralysis, severe headache with fever
 Retinopathy (noninflammatory eye disorder)
 Loss of sexual drive, impotence, male breast enlargement (gynaecomastia), defective
sperm formation, menstrual disorder, vaginal discharge
 Enlargement of lymphatic nodes (lymphoma)
Not known: frequency cannot be estimated from the available data
 Leukoencephalopathy (a disease of the white brain substance)
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, pharmacist or nurse. This includes any
possible side effects not listed in this leaflet. You can also report side effects directly via the
Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
By reporting side effects, you can help provide more information on the safety of this
medicine.




Medicines should not be disposed via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer required. The measures will help to
protect the environment.
If this medicine becomes discoloured or show signs of any deterioration, you should
seek the advice of your pharmacist.


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.
− 1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10mg methotrexate.
− 1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15mg methotrexate.
− 1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20mg methotrexate.
− 1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25mg methotrexate.
 The other ingredients are sodium chloride, sodium hydroxide, water for injections.
What Metoject looks like and contents of the pack
Metoject pre-filled syringe contains a clear yellow-brown solution for injection.
Metoject pre-filled syringe is made of colourless glass of 1 ml capacity with attached s.c.
injection needle and alcohol pads. Plunger stoppers of rubber and polystyrene rods
inserted on the stopper to form the syringe plunger.
The following pack sizes are available:
Pre-filled syringes with attached sc. injection needles, graduation and alcohol pads
containing 0.20 ml, 0.30 ml, 0.40 ml and 0.50 ml solution for injection in packs of 1 and 4
pre-filled syringes.
PL No: 15814/1035

Metoject® 50mg/ml solution for injection

POM

Metoject is manufactured by medac Gesellschaft für klinische Spezialpräparate mbH,
Theaterstr. 6, Wedel 22880, Germany. Procured from within the EU and repackaged by the
Product Licence holder: OPD Laboratories Ltd, Colonial Way, Watford, Herts WD24 4PR.
Leaflet issue and revision date (Ref): 07.07.2015.
Metoject is a registered Trademark of medac Gesellschaft für klinische Spezialpräparate
mbH, Germany.
To request a copy of this leaflet in Braille, large print or audio please call 01923 332 796.
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
Areas for subcutaneous injection
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
Abdomen
shoulder.
 Change the injection site with each injection. This may reduce
the risk of developing irritations at the injection site.
Thigh
 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
1. Unpack the methotrexate pre-filled syringe and read the package leaflet carefully.
Remove the pre-filled syringe from the packaging at room temperature.
2. Disinfection
Choose an injection site and disinfect it with a swab soaked in
disinfectant.
Allow at least 60 seconds for the disinfectant to dry.

3. 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!

4. 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.

5. 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.

5. How to store 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 or someone around you is injured by the needle, consult your doctor immediately and
do not use this pre-filled syringe.



Keep out of the sight and reach of children.
Do not store above 25°C. Keep the pre-filled syringe in the outer carton in order to
protect from light.
Do not use after the expiry date stated on the packaging. The expiry date refers to the
last day of that month.

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® 50mg/ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 50 mg methotrexate (as methotrexate disodium).
1 pre-filled syringe of 0.20 ml contains 10 mg methotrexate.
1 pre-filled syringe of 0.30 ml contains 15 mg methotrexate.
1 pre-filled syringe of 0.40 ml contains 20 mg methotrexate.
1 pre-filled syringe of 0.50 ml contains 25 mg methotrexate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection, in 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 20mg/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.
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.
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.
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
> 50
100 %
20 – 50
50 %
< 20
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 a 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).
Duration and method of administration:
The medicine is for single use only.
Metoject solution for injection 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 from oral 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 20 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, 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 applicated 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.
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).

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.
1. Examination of the mouth and throat for mucosal changes
2. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused
by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in whitecell 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.
3. 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 for 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).
4. Renal function should be monitored by renal function tests and urinanalysis (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,
which affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal antiinflammatory medicinal products) or which can potentially lead to impairment of blood formation.
Dehydration may also intensify the toxicity of methotrexate.
5. 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 methotrexateinduced 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 dosages.
6. 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 sun-burn 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.
The absence of pregnancy should be confirmed before Metoject is administered. Methotrexate causes
embryotoxicity, abortion and foetal defects in humans. Methotrexate affects spermatogenesis and
oogenesis during the period of its administration which may result in decreased fertility. These effects
appear to be reversible on discontinuing therapy. Effective contraception in men and women should be
performed during treatment and for at least six months thereafter. The possible risks of effects on
reproduction should be discussed with patients of childbearing potential and their partners should be
advised appropriately (see section 4.6).
4.5 Interaction with other medicinal products and other forms of interaction
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 drugs 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 non steroidal 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, sulphasalazine, azathioprine, ciclosporin).
Sulphasalazine
Although the combination of methotrexate and sulphasalazine can cause an increase in efficacy of
methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis
through sulphasalazine, 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, caffeinecontaining soft drinks, black tea) should be avoided during methotrexate therapy.
4.6 Fertility, pregnancy and lactation
Pregnancy
Metoject is contraindicated during pregnancy (see section 4.3). In animal studies, methotrexate has
shown reproductive toxicity (see section 5.3). Methotrexate has been shown to be teratogenic to
humans; it has been reported to cause foetal death and/or congenital abnormalities. Exposure of a
limited number of pregnant women (42) resulted in an increased incidence (1:14) of malformations
(cranial, cardiovascular and extremital). If methotrexate is discontinued prior to conception, normal
pregnancies have been reported. Women must not get pregnant during methotrexate therapy. In case
of women getting pregnant during therapy medical counselling about the risk of adverse reactions for
the child associated with methotrexate therapy should be sought. Therefore, patients of a sexually
mature age (women and men) must use effective contraception during treatment with Metoject and at
least 6 months thereafter (see section 4.4).
In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking
appropriate measures, e.g. pregnancy test, prior to initiating therapy.
Breast-feeding
Methotrexate is excreted in breast milk in such concentrations that there is a risk for the infant, and
accordingly, breast-feeding should be discontinued prior to and throughout administration.
Fertility
As methotrexate can be genotoxic, all women who wish to become pregnant are advised to consult a
genetic counselling centre, if possible, already prior to therapy, and men should seek advice about the
possibility of sperm preservation before starting therapy.
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
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)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very rare:
There have been reports of individual cases of lymphoma which subsided in a
number of cases once treatment with methotrexate had been discontinued. In a
recent study, it could not be established that methotrexate therapy increases the
incidence of lymphomas.
Blood and lymphatic system disorders
Common:
Leukopenia, anaemia, thrombopenia.
Uncommon:
Pancytopenia.
Very rare:
Agranulocytosis, severe courses of bone marrow depression.
Metabolism and nutrition disorders
Uncommon:
Precipitation of diabetes mellitus.
Nervous system disorders
Common:
Headache, tiredness, drowsiness.
Uncommon:
Dizziness, confusion, depression.
Very rare:
Impaired vision, pain, muscular asthenia or paraesthesia in the extremities,
changes in sense of taste (metallic taste), convulsions, meningism, paralysis.
Unknown:
Leukoencephalopathy.
Eye disorders
Rare:
Visual disturbances.
Very rare:
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.
Gastrointestinal disorders
Very common:
Stomatitis, dyspepsia, nausea, loss of appetite.
Common:
Oral ulcers, diarrhoea.
Uncommon:
Pharyngitis, enteritis, vomiting.
Rare:
Gastrointestinal ulcers.
Very rare:
Haematemesis, haematorrhea, toxic megacolon.
Hepatobiliary disorders (see section 4.4)
Very common:
Elevated transaminases.
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, herpes zoster,
vasculitis, herpetiform eruptions of the skin, urticaria.
Rare:
Increased pigmentation, acne, ecchymosis.
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.
Renal and urinary disorders
Uncommon:
Inflammation and ulceration of the urinary bladder, renal impairment, disturbed
micturition.
Rare:
Renal failure, oliguria, anuria, electrolyte disturbances.
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:
Allergic reactions, anaphylactic shock, allergic vasculitis, fever, conjunctivitis,
infection, sepsis, wound-healing impairment, hypogammaglobulinaemia.
Very rare:
Local damage (formation of sterile abscess, lipodystrophy) of injection site
following intramuscular or subcutaneous administration.
The appearance and degree of severity of undesirable effects depends on the dosage 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.

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 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 www.mhra.gov.uk/yellowcard.
4.9 Overdose
a) Symptoms of overdosage
Toxicity of methotrexate mainly affects the haematopoietic system.
b) Treatment measures in the case of overdosage
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 10-7 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
Distribution
Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of lowdosed 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.
Biotransformation
Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.
Elimination
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 liquor 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).
Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle
metabolite is 7-hydroxymethotrexate. 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 and 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
Do not store above 25°C. Keep the pre-filled syringe 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 attached s.c. injection needle and
alcohol pads. Plunger stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the
stopper to form the syringe plunger.
Pack sizes:
Pre-filled syringes with attached sc. injection needles, graduation and alcohol pads containing 0.20 ml,
0.30 ml, 0.40 ml and 0.50 ml solution for injection in packs of 1 and 4 pre-filled syringes.
All pack sizes are available with graduation marks.
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 health care 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 material should be disposed of in accordance with local
requirements.
Instructions for subcutaneous use
The best places for the injection are:
− upper thighs,
− abdomen except around the navel.
1. Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad).
2. Pull the protective plastic cap straight off.
3. Build a skin fold by gently squeezing the area at the injection site.
4. The fold must be held pinched until the syringe is removed from the skin after the injection.
5. Push the needle fully into the skin at a 90-degree angle.
6. Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from
the skin at the same 90-degree angle.
7. MARKETING AUTHORISATION HOLDER
Procured from within the EU and repackaged by the Product Licence holder: OPD Laboratories Ltd,
Colonial Way, Watford, Herts WD24 4PR.
8. MARKETING AUTHORISATION NUMBER
PLPI 15814/1035
9. DATE OF REVISION OF THE TEXT
07.07.2015

PACKAGE LEAFLET: INFORMATION FOR THE USER

Methotrexate 50mg/ml solution for injection
(methotrexate)
This product is available using the above name but will be referred to as Methotrexate
50mg/ml throughout the following leaflet.
Read all of this leaflet carefully before you start using this medicine because it
contains important information for you.

Other medicines and Methotrexate 50mg/ml
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.
The effect of the treatment may be affected if Methotrexate 50mg/ml is administered at the
same time as certain other drugs:



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:
1. What Methotrexate 50mg/ml is and what it is used for
2. What you need to know before you use Methotrexate 50mg/ml
3. How to use Methotrexate 50mg/ml
4. Possible side effects
5. How to store Methotrexate 50mg/ml
6. Contents of the pack and other information
1. What Methotrexate 50mg/ml is and what it is used for
Methotrexate 50mg/ml 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
Methotrexate 50mg/ml 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.
Methotrexate 50mg/ml 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 Methotrexate 50mg/ml
Do not use Methotrexate 50mg/ml if you
 are allergic to methotrexate or any of the other ingredients of this medicine (listed in
section 6).
 suffer from severe liver or kidney diseases or blood diseases.
 regularly drink large amounts of alcohol.
 suffer from a severe infection, e.g. tuberculosis, HIV or other immunodeficiency
syndromes.
 suffer from ulcers in the mouth, stomach ulcer or intestinal ulcer.
 are pregnant or breast-feeding.
 receive vaccinations with live vaccines at the same time.
Warnings and precautions
Talk to your doctor or pharmacist before taking Methotrexate 50mg/ml if:
 you are elderly or if you feel generally unwell and weak.
 your liver function is impaired.
 you suffer from dehydration (water loss).
Recommended follow-up examinations and safety measures:
Even when Methotrexate 50mg/ml 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, tests 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 Xray 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

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 Methotrexate 50mg/ml 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 Methotrexate 50mg/ml and requires an interruption of
therapy. If you suffer from diarrhoea please speak to your doctor.
Encephalopathy (a brain disorder) / leukoencephalopathy (a special disorder of the white
brain substance) have been reported in cancer patients receiving methotrexate therapy and
cannot be excluded for methotrexate therapy in other diseases.










Medicines harming the liver or the blood count, e.g. leflunomide
Antibiotics (medicines to prevent/fight certain infections) such as: tetracyclines,
chloramphenicol, and non-absorbable broadspectrum antibiotics, penicillines,
glycopeptides, sulphonamides (sulphur containing medicines that prevent/fight certain
infections), ciprofloxacin and cefalotin
Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or
inflammation)
Probenecid (medicine against gout)
Weak organic acids like loop diuretics (“water tablets”) or some medicines used for
treatment of pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and
ibuprofen) and pyrazole (e.g. metamizol for treating pain)
Medicinal products, which may have adverse effects on the bone marrow, e.g.
trimethoprim-sulphamethoxazole (an antibiotic) and pyrimethamine
Sulphasalazine (antirheumatic medicine)
Azathioprine (an immunosuppressive agent sometimes used in severe forms of
rheumatoid arthritis)
Mercaptopurine (a cytostatic agent)
Retinoids (medicine against psoriasis and other dermatological diseases)
Theophylline (medicine against bronchial asthma and other lung diseases)
Proton-pump inhibitors (medicines against stomach trouble)
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 should be avoided.
Methotrexate 50mg/ml 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 Methotrexate 50mg/ml.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a
baby, ask your doctor or pharmacist for advice before taking this medicine.
You must not take Metoject during pregnancy. There is a risk of harm to the foetus and
miscarriage. Men and women should use an effective method of birth control during
treatment and for a further six months after treatment with Metoject has been discontinued.
In women of child-bearing age, any existing pregnancy must be excluded with certainty by
taking appropriate measures, e.g. pregnancy test, prior to therapy.
As methotrexate can be genotoxic, all women who wish to become pregnant are advised to
consult a genetic counselling centre, if possible, already prior to therapy, and men should
seek advice about the possibility of sperm preservation before starting therapy.
Breast-feeding should be stopped prior to and during treatment with Methotrexate 50mg/ml.
Driving and using machines
Treatment with Methotrexate 50mg/ml 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.
Methotrexate 50mg/ml contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially
“sodium-free”.
3. How to use Methotrexate 50mg/ml
Your doctor decides on the dosage, which is adjusted individually.
Usually it takes 4 – 8 weeks before there is any effect of the treatment.
Methotrexate 50mg/ml 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. Methotrexate 50mg/ml
may be injected intramuscularly (in a muscle), intravenously (in a vein) or subcutaneously
(under the skin).
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.
Methotrexate 50mg/ml is not recommended in children less than 3 years of age due to
insufficient experience in this age group.
Method and duration of administration
Methotrexate 50mg/ml 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 Methotrexate 50mg/ml is a longterm treatment.
At the start of your therapy, Methotrexate 50mg/ml may be injected by medical staff.
In certain cases your doctor may decide to instruct you how to inject Methotrexate 50mg/ml
under the skin yourself. You will then receive appropriate training.
Under no circumstances should you try to inject Methotrexate 50mg/ml 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 health care personnel should
not handle and/or administer Methotrexate 50mg/ml.
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 have the impression that the effect of Methotrexate 50mg/ml 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, 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 (pneumonia) [common — may affect up to 1 in
10 people]
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
of the liver (liver fibrosis), fatty degeneration of the liver [all uncommon — may affect up
to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare — may affect up to 1
in 1,000 people] and liver failure [very rare — may affect up to 1 in 10,000 people]
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 — may affect up to 1 in 1,000 people]
symptoms of kidney damage such as swelling of the hands, ankles or feet or
changes in frequency of urination or decrease or absence of urine; these may be
signs of kidney failure [rare — may affect up to 1 in 1,000 people]
symptoms of infections, e.g. fever, chills, achiness, sore throat; methotrexate can
make you more susceptible to infections. Rarely [may affect up to 1 in 1,000 people]
severe infections like a certain type of pneumonia (Pneumocystis carinii pneumonia) or
blood poisoning (sepsis) may occur
severe diarrhoea, vomiting blood and black or tarry stools; these symptoms may
indicate a rare [may affect up to 1 in 1,000 people] severe complication of the
gastrointestinal system caused by methotrexate e.g. gastrointestinal ulcers
symptoms associated with the blockage (occlusion) of a blood vessel by a
dislodged blood clot (thromboembolic event) 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); methotrexate can cause thromboembolic events [rare may affect up to 1 in 1,000 people]
fever and serious deterioration of your general condition, or sudden fever
accompanied by a sore throat or mouth, or urinary problems; methotrexate can
very rarely [may affect up to 1 in 10,000 people] cause a sharp fall in white blood cells
(agranulocytosis) and severe bone marrow suppression
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 — may affect up to 1 in
10,000 people]
severe skin rash or blistering of the skin (this can also affect your mouth, eyes
and genitals); these may be signs of the very rare [may affect up to 1 in 10,000 people]
conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal
necrolysis)

In the following, please find the other side effects that may occur:
Very common: may affect more than 1 in 10 people
 Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite
 Increase in liver enzymes
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 (leukopenia, anaemia, thrombocytopenia)
Uncommon: may affect up to 1 in 100 people
 Throat inflammation, inflammation of the bowels, vomiting
 Increased sensitivity to light, loss of hair, increased number of rheumatic nodules,
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 blood cells and platelets
 Inflammation and ulcer of the urinary bladder or vagina, reduced kidney function,
disturbed urination
 Joint pain, muscle pain, osteoporosis (reduction of bone mass)
Rare: may affect up to 1 in 1,000 people
 Increased skin pigmentation, acne, blue spots due to vessel bleeding
 Allergic inflammation of blood vessels, fever, red eyes, infection, wound-healing
impairment, decreased number of anti-bodies in the blood
 Visual disturbances
 Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart
 Low blood pressure
 Lung fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the sac
around the lung
 Electrolyte disturbances
Very rare: may affect up to 1 in 10,000 people
 Profuse bleeding, toxic megacolon (acute toxic dilatation of the gut)
 Increased pigmentation of the nails, inflammation of the cuticles, furunculosis (deep
infection of hair follicles), 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
 Impaired vision, pain, loss of strength or sensation of numbness or tingling in arms and
legs, changes in taste (metallic taste), convulsions, paralysis, severe headache with fever
 Retinopathy (noninflammatory eye disorder)
 Loss of sexual drive, impotence, male breast enlargement (gynaecomastia), defective
sperm formation, menstrual disorder, vaginal discharge
 Enlargement of lymphatic nodes (lymphoma)




Medicines should not be disposed via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer required. The measures will help to
protect the environment.
If this medicine becomes discoloured or show signs of any deterioration, you should
seek the advice of your pharmacist.


6. Contents of the pack and other information
What Methotrexate 50mg/ml contains
 The active substance is methotrexate. 1 ml of solution contains methotrexate disodium
corresponding to 50 mg methotrexate.
− 1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10mg methotrexate.
− 1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15mg methotrexate.
− 1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20mg methotrexate.
− 1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25mg methotrexate.
 The other ingredients are sodium chloride, sodium hydroxide, water for injections.
What Methotrexate 50mg/ml looks like and contents of the pack
Methotrexate 50mg/ml pre-filled syringe contains a clear yellow-brown solution for injection.
Methotrexate 50mg/ml pre-filled syringe is made of colourless glass of 1 ml capacity with
attached s.c. injection needle and alcohol pads. Plunger stoppers of rubber and polystyrene
rods inserted on the stopper to form the syringe plunger.
The following pack sizes are available:
Pre-filled syringes with attached sc. injection needles, graduation and alcohol pads
containing 0.20 ml, 0.30 ml, 0.40 ml and 0.50 ml solution for injection in packs of 1 and 4
pre-filled syringes.
PL No: 15814/1035

Methotrexate 50mg/ml solution for injection

POM

Methotrexate 50mg/ml is manufactured by medac Gesellschaft für klinische
Spezialpräparate mbH, Theaterstr. 6, Wedel 22880, Germany. Procured from within the EU
and repackaged by the Product Licence holder: OPD Laboratories Ltd, Colonial Way,
Watford, Herts WD24 4PR.
Leaflet issue and revision date (Ref): 07.07.2015.
To request a copy of this leaflet in Braille, large print or audio please call 01923 332 796.
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 Methotrexate 50mg/ml pre-filled syringe
 1 alcohol pad (provided in the packaging)
Wash your hands carefully. Before use, check the Methotrexate 50mg/ml syringe for visual
defects (or cracks).
Injection site
Areas for subcutaneous injection
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
Abdomen
shoulder.
 Change the injection site with each injection. This may reduce
the risk of developing irritations at the injection site.
Thigh
 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
1. Unpack the methotrexate pre-filled syringe and read the package leaflet carefully.
Remove the pre-filled syringe from the packaging at room temperature.
2. Disinfection
Choose an injection site and disinfect it with a swab soaked in
disinfectant.
Allow at least 60 seconds for the disinfectant to dry.

3. 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!

4. 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.

Not known: frequency cannot be estimated from the available data
 Leukoencephalopathy (a disease of the white brain substance)
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, pharmacist or nurse. This includes any
possible side effects not listed in this leaflet. You can also report side effects directly via the
Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
By reporting side effects, you can help provide more information on the safety of this
medicine.

5. 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.

5. How to store Methotrexate 50mg/ml

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.



Keep out of the sight and reach of children.
Do not store above 25°C. Keep the pre-filled syringe in the outer carton in order to
protect from light.
Do not use after the expiry date stated on the packaging. The expiry date refers to the
last day of that month.

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 Methotrexate 50mg/ml.

SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Methotrexate 50mg/ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 50 mg methotrexate (as methotrexate disodium).
1 pre-filled syringe of 0.20 ml contains 10 mg methotrexate.
1 pre-filled syringe of 0.30 ml contains 15 mg methotrexate.
1 pre-filled syringe of 0.40 ml contains 20 mg methotrexate.
1 pre-filled syringe of 0.50 ml contains 25 mg methotrexate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection, in pre-filled syringe.
Clear, yellow-brown solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Methotrexate 50mg/ml 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
Methotrexate 50mg/ml 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. Methotrexate 50mg/ml 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 20mg/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.
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.
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 Methotrexate 50mg/ml for
the treatment of Crohn’s Disease in this population.
Patients with renal impairment:
Methotrexate 50mg/ml should be used with caution in patients with impaired renal function. The dose
should be adjusted as follows:
Creatinine clearance (ml/min)
Dose
> 50
100 %
20 – 50
50 %
< 20
Methotrexate 50mg/ml 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 a 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).
Duration and method of administration:
The medicine is for single use only.
Methotrexate 50mg/ml solution for injection 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 from oral 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
Methotrexate 50mg/ml 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 20 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, 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 applicated 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.
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).

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.
1. Examination of the mouth and throat for mucosal changes
2. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused
by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in whitecell 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.
3. 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 for 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).
4. Renal function should be monitored by renal function tests and urinanalysis (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,
which affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal antiinflammatory medicinal products) or which can potentially lead to impairment of blood formation.
Dehydration may also intensify the toxicity of methotrexate.
5. 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 methotrexateinduced 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 dosages.
6. 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 sun-burn 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.
The absence of pregnancy should be confirmed before Methotrexate 50mg/ml is administered.
Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Methotrexate affects
spermatogenesis and oogenesis during the period of its administration which may result in decreased
fertility. These effects appear to be reversible on discontinuing therapy. Effective contraception in men
and women should be performed during treatment and for at least six months thereafter. The possible
risks of effects on reproduction should be discussed with patients of childbearing potential and their
partners should be advised appropriately (see section 4.6).
4.5 Interaction with other medicinal products and other forms of interaction
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 drugs 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 non steroidal 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 Methotrexate
50mg/ml is administered simultaneously with other antirheumatic medicinal products (e.g. gold
compounds, penicillamine, hydroxychloroquine, sulphasalazine, azathioprine, ciclosporin).
Sulphasalazine
Although the combination of methotrexate and sulphasalazine can cause an increase in efficacy of
methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis
through sulphasalazine, 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, caffeinecontaining soft drinks, black tea) should be avoided during methotrexate therapy.
4.6 Fertility, pregnancy and lactation
Pregnancy
Methotrexate 50mg/ml is contraindicated during pregnancy (see section 4.3). In animal studies,
methotrexate has shown reproductive toxicity (see section 5.3). Methotrexate has been shown to be
teratogenic to humans; it has been reported to cause foetal death and/or congenital abnormalities.
Exposure of a limited number of pregnant women (42) resulted in an increased incidence (1:14) of
malformations (cranial, cardiovascular and extremital). If methotrexate is discontinued prior to
conception, normal pregnancies have been reported. Women must not get pregnant during
methotrexate therapy. In case of women getting pregnant during therapy medical counselling about the
risk of adverse reactions for the child associated with methotrexate therapy should be sought.
Therefore, patients of a sexually mature age (women and men) must use effective contraception
during treatment with Methotrexate 50mg/ml and at least 6 months thereafter (see section 4.4).
In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking
appropriate measures, e.g. pregnancy test, prior to initiating therapy.
Breast-feeding
Methotrexate is excreted in breast milk in such concentrations that there is a risk for the infant, and
accordingly, breast-feeding should be discontinued prior to and throughout administration.
Fertility
As methotrexate can be genotoxic, all women who wish to become pregnant are advised to consult a
genetic counselling centre, if possible, already prior to therapy, and men should seek advice about the
possibility of sperm preservation before starting therapy.
4.7 Effects on ability to drive and use machines
Central nervous symptoms such as tiredness and dizziness can occur during treatment, Methotrexate
50mg/ml has minor or moderate influence on the ability to drive and use machines.
4.8 Undesirable effects
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)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very rare:
There have been reports of individual cases of lymphoma which subsided in a
number of cases once treatment with methotrexate had been discontinued. In a
recent study, it could not be established that methotrexate therapy increases the
incidence of lymphomas.
Blood and lymphatic system disorders
Common:
Leukopenia, anaemia, thrombopenia.
Uncommon:
Pancytopenia.
Very rare:
Agranulocytosis, severe courses of bone marrow depression.
Metabolism and nutrition disorders
Uncommon:
Precipitation of diabetes mellitus.
Nervous system disorders
Common:
Headache, tiredness, drowsiness.
Uncommon:
Dizziness, confusion, depression.
Very rare:
Impaired vision, pain, muscular asthenia or paraesthesia in the extremities,
changes in sense of taste (metallic taste), convulsions, meningism, paralysis.
Unknown:
Leukoencephalopathy.
Eye disorders
Rare:
Visual disturbances.
Very rare:
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.
Gastrointestinal disorders
Very common:
Stomatitis, dyspepsia, nausea, loss of appetite.
Common:
Oral ulcers, diarrhoea.
Uncommon:
Pharyngitis, enteritis, vomiting.
Rare:
Gastrointestinal ulcers.
Very rare:
Haematemesis, haematorrhea, toxic megacolon.
Hepatobiliary disorders (see section 4.4)
Very common:
Elevated transaminases.
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, herpes zoster,
vasculitis, herpetiform eruptions of the skin, urticaria.
Rare:
Increased pigmentation, acne, ecchymosis.
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.
Renal and urinary disorders
Uncommon:
Inflammation and ulceration of the urinary bladder, renal impairment, disturbed
micturition.
Rare:
Renal failure, oliguria, anuria, electrolyte disturbances.
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:
Allergic reactions, anaphylactic shock, allergic vasculitis, fever, conjunctivitis,
infection, sepsis, wound-healing impairment, hypogammaglobulinaemia.
Very rare:
Local damage (formation of sterile abscess, lipodystrophy) of injection site
following intramuscular or subcutaneous administration.
The appearance and degree of severity of undesirable effects depends on the dosage 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.

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 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 www.mhra.gov.uk/yellowcard.
4.9 Overdose
a) Symptoms of overdosage
Toxicity of methotrexate mainly affects the haematopoietic system.
b) Treatment measures in the case of overdosage
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 10-7 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
Distribution
Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of lowdosed 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.
Biotransformation
Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.
Elimination
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 liquor 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).
Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle
metabolite is 7-hydroxymethotrexate. 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 and 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
Do not store above 25°C. Keep the pre-filled syringe 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 attached s.c. injection needle and
alcohol pads. Plunger stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the
stopper to form the syringe plunger.
Pack sizes:
Pre-filled syringes with attached sc. injection needles, graduation and alcohol pads containing 0.20 ml,
0.30 ml, 0.40 ml and 0.50 ml solution for injection in packs of 1 and 4 pre-filled syringes.
All pack sizes are available with graduation marks.
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 health care personnel should not handle and/or administer Methotrexate 50mg/ml.
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 material should be disposed of in accordance with local
requirements.
Instructions for subcutaneous use
The best places for the injection are:
− upper thighs,
− abdomen except around the navel.
1. Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad).
2. Pull the protective plastic cap straight off.
3. Build a skin fold by gently squeezing the area at the injection site.
4. The fold must be held pinched until the syringe is removed from the skin after the injection.
5. Push the needle fully into the skin at a 90-degree angle.
6. Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from
the skin at the same 90-degree angle.
7. MARKETING AUTHORISATION HOLDER
Procured from within the EU and repackaged by the Product Licence holder: OPD Laboratories Ltd,
Colonial Way, Watford, Herts WD24 4PR.
8. MARKETING AUTHORISATION NUMBER
PLPI 15814/1035
9. DATE OF REVISION OF THE TEXT
07.07.2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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