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METHOTREXATE 50 MG/ML SOLUTION FOR INJECTION

Active substance: METHOTREXATE

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5. How to store Methotrexate 50mg/ml

• KEEP OUT OF THE SIGHT AND REACH OF
CHILDREN.

• Do not store above 25°C.
• Keep the pre-filled syringes in the outer carton in




order to protect from light.
Do not use this medicine after the expiry date
stated on blister label or carton. The expiry date
refers to the last day of that month.
If your medicine becomes discoloured or show
any other signs of deterioration, ask your
pharmacist who will advise you what to do.
Medicines should not be disposed of via
wastewater or household waste. Ask your
pharmacist how to dispose of medicines no
longer required. These measures will help to
protect the environment.

6. Contents of the pack and other information
What Methotrexate 50 mg/ml contains
The active substance is methotrexate.
Each 1ml of solution contains 50mg of
methotrexate.
The other ingredients are sodium chloride, sodium
hydroxide and water for injections
What Methotrexate 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 swabs.
1 pre-filled syringe with attached sc. injection
needle, graduation and alcohol pad containing
0.2ml, 0.3ml, 0.4ml and 0.5ml solution for
injection in packs of 4 syringes.
For i.m and i.v use, a needle suitable for these
routes of administration must be used: The needle
enclosed in the pack is suitable for s.c. use only.
Manufacturer and Licence Holder
Manufactured by medac Gesellschaft fur klinische
Spezialpraparate mbH, Theaterstr. 6, 22880
Wedel, Germany and is procured from within the
EU and repackaged by the Product Licence
Holder: Lexon (UK) Limited, Unit 18, Oxleasow
Road, East Moons Moat, Redditch,
Worcestershire, B98 0RE.
If you have any questions or are not sure about
anything, ask your doctor or pharmacist. They will
have additional information about this medicine
and will be able to advise you.

POM
PL 15184/1510 -

Injection site
Areas for
subcutaneous
injection

PATIENT INFORMATION LEAFLET

The best sites for injection are:
- upper thighs,
- abdomen except around the
navel.
• If someone is helping
you with the injection,
he/she may also give
the injection into the
back of your arms, just
below the shoulder.
• Change the injection
site with each
injection. This may
reduce the risk of
developing irritations
at the injection site.
• Never inject into skin
that is tender,
bruised, red, hard, scarred or where you have
stretch marks. If you have psoriasis, you should try
not to inject directly into any raised, thick, red or
scaly skin patches or lesions.
Injecting the solution
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
Methotrexate 50mg/ml
solution for injection

Leaflet revision date: 17/06/15

Blind or partially sighted?
Is this leaflet hard to see or read?
Phone Lexon (UK) Limited,
Tel: 01527 505414 for help.
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 pre-filled syringe
• 1 alcohol pad (provided in the packaging)
Wash your hands carefully. Before use, check the
Methotrexate 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 pre-filled syringe must be in
accordance with local requirements. Pregnant
healthcare personnel should not handle and/or
administer Methotrexate.

Ref: 1510/170615/1/F

Methotrexate 50mg/ml solution for injection
(methotrexate)
Read all of this leaflet carefully before you
start using this medicine because it contains
important information for you.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your
doctor or pharmacist.
• This medicine has been prescribed for you only.
Do not pass it on to others. It may harm them,
even if their signs of illness are the same as
yours.
• If you get any side effects, talk to your doctor or
pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
Your medicine is called Methotrexate 50mg/ml
solution for injection but will be referred to as
Methotrexate 50mg/ml throughout the rest of this
leaflet.
What is in this leaflet:
1. What Methotrexate 50 mg/ml is and what it is
used for
2. What you need to know before you use
Methotrexate 50 mg/ml
3. How to use Methotrexate 50 mg/ml
4. Possible side effects
5. How to store Methotrexate 50 mg/ml
6. Contents of the pack and other information
1. What Methotrexate 50mg/ml 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 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.
• 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 50 mg/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 50 mg/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 50 mg/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 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 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 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 Methotrexate 50
mg/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.
Other medicines and Methotrexate 50 mg/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 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
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 50 mg/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 50 mg/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 Methotrexate 50 mg/ml 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
Methotrexate 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 Methotrexate 50 mg/ml.
Driving and using machines
Treatment with Methotrexate 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.
Methotrexate 50 mg/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 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.
Methotrexate 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.
Methotrexate 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 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 is a long-term treatment.
At the start of your therapy, Methotrexate may be
injected by medical staff. In certain cases your
doctor may decide to instruct you how to inject
Methotrexate under the skin yourself. You will then
receive appropriate training.
Under no circumstances should you try to inject
Methotrexate 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 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
Methotrexate 50 mg/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 (non inflammatory 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.
Ref: 1510/170615/1/B

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
low-dosed administration (dosages between 7.5
mg/m² and 80 mg/m² body surface area), the
mean bioavailability is approx. 70 %, but
considerable interindividual and intraindividual
deviations are possible (25 – 100 %). Maximum
serum concentrations are achieved after 1 – 2
hours.
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
See expiry date on carton
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.

Ref: 1510HC/170615/1/F

SUMMARY OF PRODUCT CHARACTERISTICS
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 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 a 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 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.
- mild to moderate Crohn’s disease either alone or
in combination with corticosteroids in adult
patients refractory or intolerant to thiopurines.

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 swabs.
Pack sizes:
1 pre-filled syringe with attached sc. injection
needle, graduation and alcohol pad containing
0.2ml, 0.3ml, 0.4ml and 0.5ml solution for
injection in packs of 4 syringes.
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 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. PRODUCT LICENCE HOLDER
Lexon (UK) Limited, Unit 18, Oxleasow Road,
East Moons Moat, Redditch, Worcestershire,
B98 0RE.
8. PRODUCT LICENCE NUMBER
PL 15184/1510
10. DATE OF REVISION OF THE TEXT
17/06/2015

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
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 50 mg/ml for
the treatment of Crohn’s Disease in this
population.
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
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 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.

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.

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.

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.

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, nonproductive
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.

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 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 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 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
7-hydroxymethotrexate with myalgia and
shivering was reported in one case.
Theophylline
Methotrexate may decrease the clearance of
theophylline; theophylline levels should be
monitored when used concurrently with
methotrexate.
Caffeine- or theophylline-containing beverages
An excessive consumption of caffeine- or
theophylline-containing beverages (coffee,
caffeine-containing soft drinks, black tea) should
be avoided during methotrexate therapy.
4.6 Fertility, pregnancy and lactation
Pregnancy
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.
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 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)
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.
Ref: 1510HC/170615/1/B

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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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