METHOTREXATE 50 MG/ML SOLUTION FOR INJECTION

Active substance: METHOTREXATE

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PATIENT INFORMATION LEAFLET

2529
07.10.13[2]

Metoject® 50 mg/ml solution for injection
(methotrexate)
Read all of this leaflet carefully before you start using this
medicine.
 Keep this leaflet. You may need to read it again.
 If you have any further questions, please ask your doctor or
pharmacist.
 This medicine has been prescribed for you. Do not pass it on to others.
It may harm them, even if their symptoms are the same as yours.
 If any of the side effects gets serious, or if you notice any side effects
not listed in this leaflet, please tell your doctor or pharmacist.
This medicine is available using the above name but will be referred to
as Metoject 50 mg/ml throughout the leaflet
In this leaflet:
1. What Metoject 50 mg/ml is and what it is used for
2. Before you use Metoject 50 mg/ml
3. How to use Metoject 50 mg/ml
4. Possible side effects
5. How to store Metoject 50 mg/ml
6. Further information
1. What Metoject 50 mg/ml is and what it is used for
Metoject 50 mg/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.
Rheumatoid arthritis (RA) is a chronic collagen disease, characterised by
inflammation of the synovial membranes (joint membranes). These
membranes produce a fluid which acts as a lubricant for many joints.
The inflammation causes thickening of the membrane and swelling of
the joint.
Juvenile arthritis concerns children and adolescents less than 16 years.
Polyarthritic forms are indicated if 5 or more joints are affected within the
first 6 months of the disease.
Psoriatic arthritis is a kind of arthritis with psoriatic lesions of the skin and
nails, especially at the joints of fingers and toes.
Psoriasis is a common chronic skin disease, characterised by red
patches covered by thick, dry, silvery, adherent scales.
Metoject 50 mg/ml modifies and slows down the progression of the
disease.
2. Before you use Metoject 50 mg/ml
Do not use Metoject 50 mg/ml if you
 are allergic (hypersensitive) to methotrexate or any of the other
ingredients of Metoject 50 mg/ml.
 suffer from liver or severe 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 stomach ulcer or intestinal ulcer.
 are pregnant or breast-feeding.
 receive vaccinations with live vaccines at the same time.
Take special care with Metoject 50 mg/ml
 if you are elderly or if you feel generally unwell and weak.
 if you have problems with the way your liver works.
 if you suffer from dehydration (water loss).
Recommended follow-up examinations and safety measures:
Even when Metoject 50 mg/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 X-ray will be taken.

During therapy:
You will have the following tests at least once a month during the first six
months and at least every three months thereafter:
 Examination of the mouth and throat for alterations of the mucosa
 Blood tests
 Check if your liver is working properly
 Check if your kidneys are working properly
 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 50 mg/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 Metoject 50 mg/ml and requires an
interruption of therapy. If you suffer from diarrhoea please speak to your
doctor.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently
taken any other medicines, including medicines obtained without a
prescription. Please note that this also applies to medicines that you will
take in the future.
The effect of the treatment may be affected if Metoject 50 mg/ml is
administered at the same time as certain other drugs:
 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 broad-spectrum
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.
Using Metoject 50 mg/ml with food and drink
Alcohol as well as large amounts of coffee, caffeine-containing soft
drinks and black tea should be avoided during treatment with Metoject
50 mg/ml.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
You must not take Metoject 50 mg/ml during pregnancy. Men and
women should use an effective method of birth control during treatment
and during a further six months after treatment with Metoject 50 mg/ml
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 50 mg/ml.
Driving and using machines
Treatment with Metoject 50 mg/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.
Important information about some of the ingredients of Metoject
50 mg/ml
This medicinal product contains less than 1 mmol sodium (23 mg) per
dose, i.e. essentially “sodium-free”.
3. How to use Metoject 50 mg/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.
Metoject 50 mg/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. Metoject 50 mg/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.
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 and psoriatic arthritis with Metoject is a long-term treatment.
At the start of your therapy, Metoject may be injected by medical staff.
In certain cases your doctor may decide to instruct you how to inject
Metoject 50 mg/ml 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 50
mg/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 Metoject 50 mg/ml is too
strong or too weak, you should talk to your doctor or pharmacist.
4. Possible side effects
Like all medicines, Metoject 50 mg/ml 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.
The most relevant side effects are effects on the blood forming system
and the gastrointestinal tract.
The following categories are used in order to organise the adverse
effects in order of frequency:
Very common: side effects that occur in more than 1 out of 10 patients.
Common: side effects that occur in less than 1 out of 10 patients but in
more than 1 out of 100 patients.
Uncommon: side effects that occur in less than 1 out of 100 patients but
in more than 1 out of 1,000 patients.
Rare: side effects that occur in less than 1 out of 1,000 patients but in
more than 1 out of 10,000 patients.
Very rare: side effects that occur in less than 1 in 10,000 patients.

The following side effects may occur:
Very common:
 Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite
 Increase in liver enzymes

Methotrexate may cause serious (sometimes life-threatening) side
effects. Therefore, your doctor will do tests to check for abnormalities
developing in the blood (e.g. low white blood cells, low platelets,
lymphoma) and changes in the kidney and the liver.

Common:
 Mouth ulcers, diarrhoea
 Rash, reddening of the skin, itching
 Headache, tiredness, drowsiness
 Pneumonia ([allergic] inflammation of the lungs) may occur (symptoms
are: dry, non-productive cough, shortness of breath and fever)
 Reduced blood cell formation with decrease in white and/or red blood
cells and/or platelets (leukopenia, anaemia, thrombocytopenia)

If any of the side effects gets serious, or if you notice any side effects not
listed in this leaflet, please tell your doctor or pharmacist.

Uncommon:
 Throat inflammation, inflammation of the bowels, vomiting
 Increased sensitivity to light, loss of hair, increased number of
rheumatic nodules, shingles, inflammation of blood vessels, herpeslike skin rash, hives
 Onset of diabetes mellitus
 Dizziness, confusion, depression
 Liver cirrhosis (chronic liver damage), formation of scar tissue of the
liver, fatty degeneration of the liver, 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)

Do not use after the expiry date stated on the packaging. The expiry
date refers to the last day of that month.

Rare:
 Gastrointestinal ulcers
 Increased skin pigmentation, acne, blue spots due to vessel bleeding
 Allergic reactions, allergic shock, allergic inflammation of blood
vessels, fever, red eyes, infection, blood poisoning, wound-healing
impairment, decreased number of anti-bodies in the blood
 Visual disturbances
 Acute hepatitis (inflammation of the liver)
 Inflammation of the sac around the heart, accumulation of fluid in the
sac around the heart
 Low blood pressure, occlusion of a blood vessel by dislodged blood
clot (thromboembolic events)
 Lung fibrosis, pneumonia with a specific germ (Pneumocystis carinii
pneumonia), shortness of breath and bronchial asthma, accumulation
of fluid in the sac around the lung
 Kidney failure, decrease or absence of urine, electrolyte disturbances
Very rare:
 Haematemesis (vomiting blood), profuse bleeding, toxic megacolon
(acute toxic dilatation of the gut)
 Skin blisters in connection with fever, burned skin syndrome,
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 (non- inflammatory eye disorder)
 Liver failure
 Sharp fall in white blood cells, severe bone marrow depression
 Loss of sexual drive, impotence, male breast enlargement
(gynaecomastia), defective sperm formation, menstrual disorder,
vaginal discharge
 Enlargement of lymphatic nodes (lymphoma)
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.
Metoject 50 mg/ml may cause a reduction in the number of white blood
cells and your resistance to infection may be decreased. If you
experience an infection with symptoms such as fever and serious
deterioration of your general condition, or fever with local infection
symptoms such as sore throat/sore pharynx/sore mouth or urinary
problems you should see your doctor immediately. A blood test will be
taken to check for possible reduction of white blood cells
(agranulocytosis). It is important to inform your doctor about your
medicine.

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 shoulder.
 Change the injection site with each
injection. This may reduce the risk of
developing irritations at the injection
site.
 Never inject into skin that is tender,
bruised, red, hard, scarred or where
you have stretch marks.
If you have psoriasis, you should try
not to inject directly into any raised,
thick, red or scaly skin patches or
lesions.

5. How to store Metoject 50 mg/ml
Keep out of the sight and reach of children.
Do not store above 25 °C.
Keep the pre-filled syringes in outer carton in order to protect from light.

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
6. Further information
What Metoject 50 mg/ml contains
 The active substance is methotrexate.
1 ml of solution contains 50 mg methotrexate as (methotrexate
disodium).
1 syringe (0.20 ml) contains methotrexate disodium equivalent to
10 mg methotrexate.
1 syringe (0.30 ml) contains methotrexate disodium equivalent to
15 mg methotrexate.
1 syringe (0.40 ml) contains methotrexate disodium equivalent to
20 mg methotrexate.
1 syringe (0.50 ml) contains methotrexate disodium equivalent to
25 mg methotrexate.
 The other ingredients are sodium chloride, sodium hydroxide, water for
injections.
What Metoject 50 mg/ml looks like and contents of the pack
A pre-filled colourless glass syringe of 1 ml capacity, filled with a clear,
yellow-brown solution. It is embedded with an injection needle with a
plunger stopper of rubber and plastic rods inserted on the stopper to
form the syringe. Also contains alcohol pads.
The following pack sizes are available:
Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 m and 0.50 ml of
solution are available in a packsize of 1 syringe with embedded SC
needle.
Alcohol pads included in the package.

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
prefilled syringe!

4. Inserting the cannula

Product Licence Holder and Manufacturer
Manufactured by medac Gesellschaft für klinische Spezialpräparate
mbH, Theaterstr. 6, 22880 Wedel, Germany and procured from the EU
by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge
Close, Harrow, Middlesex HA1 1XD. Repackaged by Servipharm Ltd.
POM

Using two fingers, pinch up a fold of skin and
quickly insert the needle into the skin at a 90degree angle.

PL 20636/2529
5. Injection

Leaflet issue and revision date (Ref): 07.10.13[2]
Metoject is trademark of medac Gesellschaft für klinische
Spezialpräparate mbH.
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 50 mg/ml 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).

Insert the needle fully into the fold of skin.
Push the plunger down slowly and inject the
liquid underneath your skin. Hold the skin
securely until the injection is completed.
Carefully pull the needle straight out.

Methotrexate should not come into contact with the surface of the skin or
mucosa. In the event of contamination, the affected area must be rinsed
immediately with plenty of water.
If you or someone around you is injured by the needle, consult your
doctor immediately and do not use this pre-filled syringe.
Disposal and other handling
The manner of handling and throwing away of the medicine and prefilled syringe must be in accordance with local requirements. Pregnant
healthcare personnel should not handle and/or administer Metoject.

SUMMARY OF PRODUCT CHARACTERISTICS

2529
07.10.13[S-2]

1. NAME OF THE MEDICINAL PRODUCT
Metoject 50 mg/ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 1 ml of solution contains 50 mg methotrexate as (methotrexate disodium).
1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10 mg methotrexate.
1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15 mg methotrexate.
1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20 mg methotrexate.
1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25 mg methotrexate.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Clear, yellow-brown solution.
Solution for injection, in pre-filled syringe.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Metoject 50 mg/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 antiinflammatory 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.
4.2 Posology and method of administration
Metoject 50 mg/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. Metoject 50 mg/ml is injected once weekly.
The patient is to be explicitly informed about the unusual 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
2
The recommended dose is 10-15 mg/m body surface area (BSA)/once weekly. In therapy-refractory cases the
2
weekly dosage may be increased up to 20mg/m 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 are 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.
Patients with renal impairment:
Metoject 50 mg/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
Metoject 50 mg/ml must not be used
See section 4.3
The dose should be increased as necessary but should in general not exceed the maximum recommended
weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should not
exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.
Patients with 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 50 mg/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
Metoject 50 mg/ml is contraindicated in the case of
- hypersensitivity to methotrexate or to any of the excipients,
- 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 white-cell or
platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy.
Patients should be advised to report all signs and symptoms suggestive of infection. Patients taking
simultaneous administration of haematotoxic medicinal products (e.g. leflunomide) should be monitored
closely with blood count and platelets.
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 anti-inflammatory 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 to other forms of therapy, but only when the diagnosis has been
established by biopsy and/or after dermatological consultation.
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 50 mg/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 antiinflammatory 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, trimethoprimsulphamethoxazole) 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 50 mg/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 7hydroxymethotrexate with myalgia and shivering was reported in one case.
Theophylline
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used
concurrently with methotrexate.
Caffeine- or theophylline-containing beverages
An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing soft
drinks, black tea) should be avoided during methotrexate therapy.
4.6 Pregnancy and lactation
Metoject 50 mg/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 Metoject 50 mg/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.
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.
Lactation: 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.
4.7 Effects on ability to drive and use machines
Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metoject 50 mg/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)
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.
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.
General disorders and administration site conditions
Rare: Allergic reactions, anaphylactic shock, allergic vasculitis, fever, conjunctivitis, infection, sepsis, woundhealing impairment, hypogammaglobulinaemia.
Very rare: Local damage (formation of sterile abscess, lipodystrophy) of injection site following intramuscular or
subcutaneous administration.
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.
Eye disorders
Rare: Visual disturbances.
Very rare: Retinopathy.
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.
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.
Blood and lymphatic system disorders
Common: Leukopenia, anaemia, thrombopenia.
Uncommon: Pancytopenia.
Very rare: Agranulocytosis, severe courses of bone marrow depression.
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.
Musculoskeletal and connective tissue disorders
Uncommon: Arthralgia, myalgia, osteoporosis.
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.

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.
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
-7
until the serum levels of methotrexate are below 10 mol/l.
In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of
methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been
shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute,
intermittent haemodialysis using a high flux dialyser.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Folic acid analogues
ATC code: L01BA01
Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and polyarthritic
forms of juvenile idiopathic arthritis.
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 and chronic polyarthritis, 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.
5.2 Pharmacokinetic properties
Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-dosed
2
2
administration (dosages between 7.5 mg/m and 80 mg/m body surface area), the mean bioavailability is
approx. 70 %, but considerable interindividual and intraindividual deviations are possible (25 – 100 %).
Maximum serum concentrations are achieved after 1 – 2 hours.
Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.
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 syringes in the outer carton in order to protect from light.
6.5 Nature and contents of container
Nature of container:
A pre-filled colourless glass syringe of 1 ml capacity, filled with a clear, yellow-brown solution. It is embedded
with an injection needle with a plunger stopper of rubber and plastic rods inserted on the stopper to form the
syringe. Also contains alcohol pads.
Pack sizes:
The following pack sizes are available:
Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 m and 0.50 ml of solution are available in a packsize of 1
syringe with embedded SC needle. Alcohol pads included in the package.
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 50 mg/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 product or waste 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 the EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow,
Middlesex HA1 1XD. Repackaged by Servipharm Ltd.
8. MARKETING AUTHORISATION NUMBER
PL 20636/2529
9. DATE OF REVISION OF THE TEXT
07.10.13[S-2]

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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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