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METHOFILL 50MG/ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE

Active substance(s): METHOTREXATE

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Methofill 50mg/ml solution for
injection in pre-filled syringe
methotrexate
Read all of this leaflet carefully before you start using this medicine
because it contains important information for you.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist or
nurse.
• 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 or nurse.
This includes any possible side effects not listed in this leaflet. See
section 4.
What is in this leaflet:
1. What Methofill is and what it is used for
2. What you need to know before you use Methofill
3. How to use Methofill
4. Possible side effects
5. How to store Methofill
6. Contents of the pack and other information

1. What Methofill is and what it is used for
Methofill contains methotrexate as active substance
Methotrexate is a substance with 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
Methofill 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 psoriatric 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.
Methofill 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
Methofill
Do not use Methofill 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 or nurse before taking Methofill if:
• you are elderly or if you feel generally unwell and weak.
• you have problems with the way your liver works.
• you suffer from dehydration (water loss).
Recommended follow-up examinations and safety measures:
Even when Methofill 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:

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 Methofill pre-filled syringe with needle safety guard

• 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 Methofill 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.

Use in children and adolescents
The doctor decides on the appropriate dose in children and adolescents
with polyarthritic forms of juvenile idiopathic arthritis.
Methofill is not recommended in children less than 3 years of age due to
insufficient experience in this age group.
Method and duration of administration
Methofill 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 Methofill is a
long-term treatment.

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

At the start of your therapy, Methofill may be injected by medical staff. In
certain cases your doctor may decide to instruct you how to inject
Methofill under the skin yourself. You will then receive appropriate training.

Diarrhoea can be a toxic effect of Methofill and requires an interruption of
therapy. If you suffer from diarrhoea please speak to your doctor.

Under no circumstances should you try to inject Methofill yourself before
you have received such training.

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 disease.

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

Other medicines and Methofill
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 Methofill is administered at
the same time as certain other drugs:

Please note that all of the contents have to be used.
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 Methofill .
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.

• 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)

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

Vitamins containing folic acid may impair the effect of your treatment and
should only be taken when advised by your doctor.

• 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)

Vaccination with live vaccine should be avoided.
Methofill 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 Methofill.
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 Methofill 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 during a further six months
after treatment with Methofill 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 has to be stopped prior to and during treatment with
Methofill.
Driving and using machines
Treatment with Methofill 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.
Methofill contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per
dose, i.e. essentially “sodium-free”.

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

If you forget to use Methofill
Do not take a double dose to make up for a forgotten dose.
If you stop using Methofill
If you stop using Methofill , talk to your doctor immediately.
If you have the impression that the effect of Methofill 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:

Methofill is administered subcutaneously (under the skin) 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.

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

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

Injecting the solution

Injection site

1. Unpack the methotrexate pre-filled syringe with prefixed needle safety
guard and read the package leaflet carefully. Remove the pre-filled
syringe with prefixed needle safety guard from the packaging at room
temperature.

3. Ensure the system is intact/ not damaged

Do not use the product:
- If you see any damage (syringe or needle safety guard breakage) or lose
components;
- If the needle safety guard is on safety position before use as shown on
picture 7 because this indicate system already operated.
In general the needle safety guard should not be used if it does not
conform to the figure on the left side.
If so discard the needle safety guard in a biohazard (sharps) container
4. Remove the protective cap

2. Disinfection

Choose an injection site and disinfect it with a alcohol swab. Allow at least
60 seconds for the disinfectant to dry.

Note: PIL is required centrally folded in bible paper

- Hold the body of the needle safety guard in one hand with the needle
end pointing away from you and without touching the plunge rod;
- Pull the needle cap straight off with your other hand;
- After removal, throw away the needles cap in a biohazard (sharps)
container.

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

The following pack sizes are available:

Very common: may affect more than 1 in 10 people
• Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite
• Increase in liver enzymes

• For 0.15 mL, 0.20 mL, 0.30 mL and 0.40 mL: packs containing 1, 2, 4, 5,
6, 8, 10, 12 and 24 prefilled syringe(s) with fixed needle covered with
rigid needle shield. Further pre-filled syringes prefixed with needle safety
guard.

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)

• For 0.25 mL, 0.35 mL, 0.45 mL, 0.55 mL and 0.60 mL: packs containing
1, 4, 5, 6, 8 and 12 prefilled syringe(s) with fixed needle covered with
rigid needle shield. Further pre-filled syringes prefixed with needle safety
guard.

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, woundhealing 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
• Impaired vision, pain, loss of strength or sensation of numbness or
tingling in arms and legs, changes in taste (metallic taste), convulsions,
paralysis, severe headache with fever
• Retinopathy (noninflammatory eye disorder)
• Loss of sexual drive, impotence, male breast enlargement (gynaecomastia),
defective sperm formation, menstrual disorder, vaginal discharge
• Enlargement of lymphatic nodes (lymphoma)

• For 0.50 mL: packs containing 1, 2, 4, 5, 6, 8, 10 and 12 prefilled
syringe(s) with fixed needle covered with rigid needle shield. Further
pre-filled syringes prefixed with needle safety guard.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Accord Healthcare Limited,
Sage House, 319 Pinner Road,
North Harrow,
Middlesex, HA1 4HF,
United Kingdom
Manufacturer:
Accord Healthcare Limited,
Sage House, 319 Pinner Road,
North Harrow,
Middlesex, HA1 4HF,
United Kingdom
Wessling Hungary Kft.,
Fóti út 56., Budapest 1047,
Hungary
This leaflet was last revised in 07/2016

Not Known: frequency cannot be estimated from the available data:
• Leukoencephalopathy (a disease of the white brain substance)
Subcutaneous application of methotrexate is locally well tolerated. Only
mild local skin reactions (such as burning sensations, erythema, swelling,
discolouration, severe itching, pain) 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
United Kingdom
The Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard.
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie

5. How to store Methofill
Keep this medicine out of the sight and reach of children.
Store below 30 °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 which is stated on the
label/carton after EXP. The expiry date refers to the last day of that month.
Do not use Methofill if you notice sign of colour change or contain visible
particles.
Do not throw away any medicines via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use.
These measures will help protect the environment.

6. Contents of the pack and other information
What Methofill contains
• The active substance is methotrexate. 1 ml of solution contains
methotrexate disodium corresponding to 50 mg methotrexate.
• The other ingredients are sodium chloride, sodium hydroxide (for pH
adjustment) and water for injections.
What Methofill looks like and contents of the pack
Methofill pre-filled syringes contain a clear, yellow to brown solution.
Pre-filled syringes prefixed with needle safety guard. Package containing
pre-filled syringe (s), with or without blister and alcohol swab. The blister
packs are for individual syringes with prefixed needle safety guard.

5. Insert the Needle

- Place the thumb on the plunger rod head;
- Depress the plunger rod and push firmly at the end of the injection to
ensure that syringe emptying is completed. Hold the skin securely until
the injection is completed.

Once the syringe has been used, immediately discard the needle safety
guard into biohazard (sharp) containers.
Do not throw away the used Needle safety guard in a household
trash.

7. Needle stick protection
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.
- Lightly pinch the skin at the injection site with one hand;
- With the other hand insert the needle into the injection site without
touching the plunger rod head (for instance with 90 degree angle).

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

6. Injection
The safety system will activate once the plunger rod is fully depressed:
- Keep the syringe still and slowly lift your thumb off of the plunger rod
head;
- The plunger rod will move up with your thumb and the spring retracts the
needle from the site, into the Needle safety guard.

Disposal and other handling
The manner of handling and throwing away of the medicine and pre-filled
syringe must be in consistent with that of other cytostatic preparations in
accordance with local requirements. Pregnant healthcare personnel
should not handle and/or administer Methofill .

8. Discard the Needle safety guard

INP012
10 00000 0 000000

Note: PIL is required centrally folded in bible paper

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