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METHOTREXATE 25 MG/ML SOLUTION FOR INJECTION PRE-FILLED SYRINGE

Active substance(s): METHOTREXATE

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PACKAGE LEAFLET: INFORMATION FOR THE USER

hameln

Methotrexate 25 mg/ml solution for injection, pre-filled syringe
Methotrexate
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness
are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effect not listed in this leaflet,
In this leaflet:
1. What Methotrexate is and what it is used for
2. What you need to know before you use Methotrexate
3. How to use Methotrexate
4. Possible side effects
5. How to store Methotrexate
6. Contents of the pack and other information
1. WHAT METHOTREXATE IS AND WHAT IT IS USED
FOR
Methotrexate is a drug with the following properties:
- it interferes with the growth of certain cells in the body that
reproduce quickly (anti-tumour agent),
- it reduces undesired reactions of the body’s own defence
mechanism (immunosuppressant), and
- it has anti-inflammatory effects.
Methotrexate is used for the treatment of:
- active rheumatoid arthritis (RA) in adult patients where
treatment with disease modifying antirheumatic drugs
(DMARDs) is indicated.
- polyarthritic forms (when five or more joints are involved)
of severe, active juvenile idiopathic arthritis (JIA) when
the response to so-called non-steroidal anti-inflammatory
drugs (NSAIDs) has been inadequate
- severe forms of psoriasis, which cannot be sufficiently
treated with conventional therapy such as phototherapy,
PUVA, and retinoids, and severe psoriasis affecting the
joints (psoriatic arthritis).
2. WHAT YOU NEED TO KNOW BEFORE YOU USE
METHOTREXATE
Important warning with reference to the dosing of
methotrexate:
Methotrexate for the therapy of rheumatic diseases or
diseases of the skin must only be used once weekly.
Incorrect dosing of methotrexate may lead to serious
adverse effects including a fatal outcome. Please read
section 3 of this Leaflet very carefully.
Please ask your doctor or pharmacist before using
Methotrexate if you have any questions.
Do not use Methotrexate
- if you are allergic to Methotrexate, or any of the other
ingredients of this medicine (listed in section 6).
- if you have significant kidney disease (your doctor decides
the severity of your disease).
- if you have significant liver disease (your doctor decides the
severity of your disease) .
- if you have disorders of the blood-forming system.
- if you have increased alcohol consumption.
- if you have an impaired immune system.
- if you have severe or existing infections, e.g. tuberculosis
and HIV.
- if you have gastrointestinal ulcers.
- if you are pregnant or breast-feeding (see section
“Pregnancy, breast-feeding and male fertility”).
You should not be given live vaccines during treatment with
Methotrexate.
Warning and precautions
Talk to your doctor or pharmacist before using
Methotrexate
- if you have diabetes mellitus treated with insulin.
- if you have inactive, prolonged infections (e.g. tuberculosis,
hepatitis B or C, shingles [herpes zoster]).
- if you have or have had any liver or kidney disease.
- if you have problems with your lung function.
- if you are severely overweight.
- if you have abnormal accumulation of liquid in the
abdomen, in the cavity between the lungs and chest wall
(ascites, pleural effusions).
- if you are dehydrated or suffer from conditions leading to
dehydration (vomiting, diarrhoea, stomatitis).
The therapy is to be administered once a week.
Incorrect intake of methotrexate can lead to severe,
including potentially lethal, side effects.
Read section 3 of this package leaflet carefully.
If you experienced problems with your skin after radiation
therapy (radiation induced dermatitis) and sun-burn, these
conditions can reappear under methotrexate therapy (recallreaction).
Children, adolescents and elderly
Dosage instructions for children and adolescents with
polyarthritic forms of juvenile idiopathic arthritis depend on
patients body surface area.
Use in children below 3 years of age is not recommended due
to the insufficient experience in this age group.
Children and the elderly should be kept under particularly
close medical surveillance during treatment with Methotrexate,
in order to identify possible side effects as early as possible.
Dosage for elderly patients should be relatively low due to
age-related reduced liver and kidney function and low folate
reserves.
Special precautionary measures during treatment with
Methotrexate:
Methotrexate should only be prescribed by doctors with
sufficient experience in the Methotrexate treatment of the
disease concerned.
Methotrexate temporarily affects sperm and egg production.
You and your partner must avoid conception (becoming
pregnant or fathering children) if currently receiving
methotrexate and for at least six months after your treatment
with methotrexate has stopped (see also section “Pregnancy,
breast-feeding and male fertility”).
Skin changes caused by psoriasis can worsen during
treatment with Methotrexate if exposure to UV irradiation
occurs at the same time.
Recommended follow up examinations and precautions:
Even if Methotrexate is administered at low doses, severe
side effects can occur. In order to diagnose them early, regular
monitoring by the doctor at short-term intervals is necessary.
Before treatment is started your doctor may carry out blood
tests, and also check how well your kidneys and liver are
working. You may also have a chest X-ray. Further tests
may also be done during and after treatment. Do not miss
appointments for blood tests.
If the results of any of these tests are abnormal, treatment will
only be resumed when all readings are back to normal.
Other medicines and Methotrexate
Please tell your doctor or pharmacist if you are taking, have
recently taken or want to start taking any other medicines,
including medicines obtained without a prescription and herbal
or natural medicinal products.
Remember to tell your doctor about your treatment with
Methotrexate, if you are prescribed another medicine while
the treatment is still ongoing.
It is especially important to tell your doctor if you are using:
- other treatments for rheumatoid arthritis or psoriasis such as
leflunomide, sulfasalazine (also used for ulcerative colitis),
acetylsalicylic acid, phenylbutazone, or amidopyrine
- alcohol (should be avoided)
- live vaccinations
- azathioprine (used to prevent rejection after an organ
transplantation)
- retinoids (used to treat psoriasis and other skin disorders)
- anticonvulsant drugs (used to prevent fits)
- cancer treatments
- barbiturates (sleeping injection)
- tranquillisers
- oral contraceptives
- probenecid (used to treat gout)
- antibiotics
- pyrimethamine (used to prevent and treat malaria)
- vitamin preparations, which contain folic acid

- proton-pump inhibitors (used to treat severe heartburn or
ulcers)
- theophylline (used to treat asthma)
Methotrexate with food, drink and alcohol
During treatment with this medicine you should avoid any
alcohol consumption as well as excessive consumption of
coffee, caffeine-containing beverages, or black tea. Also
make sure you drink plenty of liquids during treatment with
Methotrexate because dehydration (reduction in body water)
can increase the toxicity of Methotrexate.
Pregnancy, breast-feeding and male fertility
Pregnancy
Do not use Methotrexate during pregnancy or if you are trying
to become pregnant. Methotrexate can cause birth defects,
harm unborn babies or cause miscarriages and so it is very
important that it is not given to pregnant patients or patients
planning to become pregnant. Therefore, in women of childbearing age any possibility of pregnancy must be excluded
with appropriate measures, e.g. a pregnancy test, before
starting treatment. You must avoid becoming pregnant whilst
taking methotrexate and for at least 6 months after treatment
is stopped. Therefore, you must ensure reliable contraception
during this whole period (see also section “Do not use
Methotrexate”).
If you do become pregnant during treatment, you should be
offered advice regarding the risk of harmful effects on the child
through treatment. If you wish to become pregnant you should
consult your doctor, who may refer you for specialist advice,
before the planned start of treatment, because methotrexate
may be genotoxic, which means that the medicine may harm
your unborn baby.
Breast-feeding
Do not breast-feed during treatment, because methotrexate
passes into breast milk. If your attending doctor considers
treatment with methotrexate as absolutely necessary during
the lactation period, you must stop breast-feeding (see also
section “Do not use Methotrexate”).
Male fertility
Methotrexate may be genotoxic. This means that the medicine
may cause genetic mutation. Methotrexate can affect sperm
production with the potential to cause birth defects. Therefore,
you must avoid fathering a child whilst taking methotrexate
and for at least 6 months after treatment is stopped. Since
treatment with methotrexate may lead to infertility, it might be
advisable for male patients to look into the possibility of sperm
preservation before starting treatment.
Driving and using machines
Tiredness and dizziness can occur during treatment. If
affected, you should not drive or operate machinery.
Important information about some of the ingredients of
Methotrexate
This medicinal product contains less than 1 mmol sodium
(23 mg) per pre-filled syringe, i.e. essentially ‘sodium-free’.
3. HOW TO USE METHOTREXATE
This medicine should only be prescribed by physicians, who
are familiar with the various characteristics of the medicinal
product and its mode of action.
Always use Methotrexate exactly as your doctor has told you.
You should check with your doctor or pharmacist if you are
unsure.
Methotrexate is administered once a week only. Together
with your doctor you should decide on a suitable fixed weekday
each week on which you receive your injection.
Incorrect intake of Methotrexate can lead to severe, including
potentially lethal, side effects.
The recommended dosage is:
Dosage in patients with rheumatoid arthritis
The recommended starting dose for methotrexate is 7.5 mg
once a week. Methotrexate is given in a single application as
injection under the skin or into a muscle (see section “Method
and duration of administration”).
In case of inadequate action and if tolerated well, Methotrexate
doses may be gradually increased by 2.5 mg per week. The
mean weekly dose is 15-20 mg. Generally, a weekly dose of
25 mg Methotrexate should not be exceeded. Upon achieving
the desired therapeutic results, the dose should be reduced
gradually to the lowest possible effective maintenance dose.
Use in children and adolescents
Dosage in children and adolescents with polyarthritic forms
of juvenile idiopathic arthritis
The recommended dose is 10-15 mg/m² body surface area per
week. In cases with inadequate response, the weekly dosage
may be increased up to 20 mg/m² body surface area/week.
However, regular check-ups should be done more often.
Use in children below 3 years of age is not recommended due
to the insufficient experience in this age group.
Dosage in adult patients with psoriasis or psoriatic arthritis
Recommended initial dose (for an average body weight of
70 kg):
It is recommended to administer a single test dose of 5-10 mg,
in order to assess possibly damaging effects.
This dose can be administered subcutaneously (under the
skin) or intramuscularly (into a muscle).
If, one week later, no blood count changes are observed,
therapy is continued with a dose of approximately 7.5 mg.
The dose may be gradually increased (in steps of 5-7.5 mg
per week and under blood count surveillance) until ideal
therapeutic results are obtained. Generally, a weekly dose of
25 mg should not be exceeded. Doses exceeding 20 mg per
week can be associated with significant increase in toxicity,
especially bone marrow suppression.
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
Upon achieving the desired therapeutic results, the dose
should be weekly reduced to the lowest possible effective
maintenance dose for the individual patient.
Patients with kidney disorders
Patients with a kidney disorder may need a reduced dose.
Method and duration of administration
For subcutaneous and intramuscular use.
Any unused solution should be discarded (see also section
“How to store Methotrexate”).
The duration of treatment is determined by the treating
physician. Methotrexate is injected once weekly! It is
recommended to specify a certain day of the week as “day
for injection”.
Methotrexate is given as injection under the skin or into a
muscle.
Treatment of rheumatoid arthritis, juvenile idiopathic arthritis,
psoriasis vulgaris and psoriatic arthritis with Methotrexate is a
long-term treatment.
Rheumatoid arthritis
Generally, improvement of the symptoms can be expected
after 4-8 weeks of treatment. Symptoms may return after
Methotrexate treatment is stopped.
Severe types of psoriasis vulgaris and psoriatic arthritis
(psoriasis arthropathica)
Generally, response to treatment can be expected after 26 weeks. Depending on symptoms severity and on laboratory
parameters, the therapy is then continued or discontinued.
At the start of your therapy, Methotrexate may be injected by a
doctor. However, your doctor may decide that it is right for you
to learn how to inject Methotrexate yourself. You will receive
appropriate training for you to do this. Under no circumstances
should you attempt to inject yourself unless you have been
trained to do so.

------------------------------------------------------------------------------------------------------------------------------------------------------------------------------The following information is intended for medical or healthcare professionals only:
PREPARATION GUIDE FOR:

hameln

Methotrexate 25 mg/ml solution for injection, pre-filled syringe
Pre-filled syringe
Methotrexate for the therapy of rheumatic or skin diseases
must only be used once weekly.
Please refer to Summary of Product Characteristics for full
prescribing and other information.

Instructions for use and handling and disposal
The solution is to be visually inspected prior to use. Only clear
solutions practically free from particles should be used.
Handling and disposal must be consistent with that of other
cytotoxic preparations in accordance with local requirements.
Pregnant health care professionals should not handle and/or
administer Methotrexate.

If you use more Methotrexate than you should
Do not change the dosage by yourself!
Use Methotrexate according to the doctor’s orders or
according to the dosage directions stated in this package
leaflet. If you use more of this medicine than you should, a
physician or nearest hospital casualty department must be
contacted immediately.
An overdose of methotrexate can lead to severe toxic
reactions. Overdose symptoms may include easy bruising or
bleeding, unusual weakness, mouth sores, nausea, vomiting,
black or bloody stools, coughing up blood or vomit that looks
like coffee grounds, and decreased urinating (see also section
”Possible side effects”).
Take your medicine package with you if you go to a doctor
or hospital. The antidote in case of an overdose is calcium
folinate.
If you forget to use Methotrexate
Do not take a double dose to make up for forgotten individual
doses, but continue taking the ordered dose. Ask your doctor
for advice.
If you stop taking Methotrexate
You should not interrupt or discontinue your treatment with
Methotrexate, unless you have discussed this with your
doctor. If you suspect severe side effects, contact your doctor
immediately for advice.
If you have any further questions on the use of this product,
ask your doctor or pharmacist.
Step-by-step instructions for subcutaneous injection:
Setting up for an injection:
• Open the box on a flat surface. Read the package leaflet
carefully.
• Take one pre-filled syringe out of the box without shaking it.
• Visually inspect the solution in the syringe.
• Choose an injection site. Wipe the injection site with an
alcohol pad, using a circular motion. Do not touch this area
before injection. You will be instructed in detail by your
doctor.
Injecting the solution:
• Remove the needle cover by firmly pulling it straight off the
syringe. Be careful not to bend or twist the cover during
removal to avoid damage to the needle.

• When you remove the needle cover, there may be a drop of
liquid at the end of the needle. This is normal. Do not touch
the needle or allow it to touch any surface. Do not touch or
bump the plunger to avoid loss of fluid.
• With two fingers, form a skin fold and puncture it almost
vertically. With a quick, short motion, push the needle
completely into the skin fold. There is no need to aspirate
prior to injection.
• Push the plunger down and inject the fluid at a slow, steady
rate.

Very rare (affects less than 1 user in 10,000) and frequency
not known:
Infections, liver disorders, low level of antibodies, severe
failure of the bone marrow (can be detected by a test carried
out by a doctor), swollen glands, sleeplessness, pain, muscle
weakness, pins and needles, breathing disorders, changes
in sense of taste (metallic taste), inflammation of the lining
of the brain causing paralysis or vomiting, red eyes, damage
to the retina of the eye, fluid on the lungs, vomiting blood,
cold sores, protein in the urine (can be detected by a test
carried out by a doctor), loss of sex drive, problems having an
erection, infection around a fingernail, severe complication of
the digestive tract, boils, small blood vessels in the skin, fungal
infections, damage to the blood vessels of the skin, lumps in
the armpit or groin, vaginal discharge, infertility, male breast
enlargement (gynaecomastia).
Other:
After injection into a muscle, there may be a burning sensation
or damage at the injection site. After injection under the skin
there may be a mild skin reaction.
Methotrexate 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). lt is
important to inform your doctor about your medicine.
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.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist.
This includes any possible side effects not listed in this leaflet.
You can also report side effects directly via the Yellow Card
Scheme at: www.mhra.gov.uk/yellowcard. By reporting side
effects you can help provide more information on the safety of
this medicine.
5. HOW TO STORE METHOTREXATE
Keep out of the reach and sight of children.
Do not use Methotrexate after the expiry date which is stated
on the label of the pre-filled syringe and the carton after
“EXP.”. The expiry date refers to the last day of that month.
Keep the pre-filled syringes in the outer carton in order to
protect from light.
Do not store above 25°C.
Do not refrigerate or freeze.
Do not use Methotrexate if you notice the solution is not clear
and free of particles or if the container is damaged.
This medicinal product must not be mixed with other medicinal
products.
The product has to be used immediately after opening.
For single use only. Any unused solution should be discarded!
Do not throw away any medicines via wastewater or household
waste. Ask your pharmacist how to dispose of medicines and
packaging no longer required. These measures will help to
protect the environment.
6. CONTENTS OF THE PACK AND OTHER INFORMATION

End of injection:
• Remove the needle. Be careful to keep it at the same angle
as inserted.

What Methotrexate contains
The active substance is methotrexate.
1 ml of solution for injection contains 25 mg methotrexate.
1 pre-filled syringe with 0.3 ml contains 7.5 mg methotrexate.
1 pre-filled syringe with 0.4 ml contains 10 mg methotrexate.
1 pre-filled syringe with 0.6 ml contains 15 mg methotrexate.
1 pre-filled syringe with 0.8 ml contains 20 mg methotrexate.
1 pre-filled syringe with 1.0 ml contains 25 mg methotrexate.
The other ingredients are: sodium chloride, sodium hydroxide
(for pH adjustment) and water for injections.
What Methotrexate looks like and contents of the pack
Methotrexate is a clear, yellowish solution for injection
available in pre-filled syringes with attached needle.
Each box contains 1 pre-filled syringe with (each) 0.3 ml,
0.4 ml, 0.6 ml, 0.8 ml or 1.0 ml solution for injection.
Marketing Authorisation Holder
hameln pharmaceuticals ltd
Gloucester
United Kingdom

• Dab the injection site with a swab. Do not rub as this will
cause irritation at the injection site.
• To avoid any injuries, carefully put the needle cover back on
the needle by gently pressing it into place.
4. POSSIBLE SIDE EFFECTS

Manufacturer
hameln rds a.s.
Horná 36, 900 01
Modra
Slovak Republic
This leaflet was last approved in 06/2015.

Like all medicines, Methotrexate can cause side effects,
although not everybody gets them.
Tell your doctor straight away if you get any sudden
wheeziness; difficulty in breathing; swelling of the eyelids, face
or lips; rash or itching (especially affecting your whole body).
Serious side effects
If you develop any of the following side effects, contact your
doctor immediately:
- lung complaints (symptoms may be general illness; dry,
irritating cough; shortness of breath, breathlessness at rest,
chest pain, or fever)
- severe peeling or blistering of the skin
- unusual bleeding (including vomiting blood) or bruising
- severe diarrhoea
- ulcers in mouth
- blistering of mucous membranes
- black or tarry stools
- blood in the urine or stools
- tiny red spots on the skin
- fever
- yellowing of the skin (jaundice)
- tenderness in the upper right area of your abdomen
- pain or difficulty in passing urine
- thirst and/or frequent urination
- fits (convulsions)
- loss of consciousness
- blurred or decreased vision
- brain disorder
The following side effects have also been reported:
Very common (affects more than 1 user in 10):
Inflammation of the mouth, indigestion, loss of appetite,
nausea (feeling sick), vomiting, tummy pain, inflammation and
ulcers in the mouth and throat, and increase in liver enzymes
(can be detected by a test carried out by a doctor).
Common (affects 1 to 10 users in 100):
Changes in the number of blood cells and platelets (can be
detected by a test carried out by a doctor), inflammation of the
lungs (pneumonia) with dry, non­ productive cough, shortness
of breath and fever, headache, tiredness, sleepiness,
diarrhoea, measles-like rash (alone), redness, and itching.
Uncommon (affects 1 to 10 users in 1,000):
Spinning sensation, confusion, depression, fits, inflammation
of blood vessels, lung damage, ulcers and bleeding in the
digestive tract, liver disorders (can be detected by a test
carried out by a doctor), diabetes, decreased blood protein
(can be detected by a test carried out by a doctor), nettle
rash (alone), light sensitivity, brown skin, hair loss, increase
of rheumatic nodules (lumps of tissues), shingles, painful
psoriasis, joint or muscle pain, brittle bones, inflammation and
ulcers in the bladder (possibly with blood in the urine), painful
urination, severe allergic reactions, inflammation and ulcers of
the vagina, slow wound healing.
Rare (affects 1 to 10 users in 10,000):
Inflammation of the lining of the heart, fluid around the
heart, severely visual disturbance, mood alterations, low
blood pressure, blood clots, sore throat, interruption of
breathing, asthma, inflammation of the digestive tract, bloody
stools, inflamed gums, abnormal digestion, acute hepatitis
(inflammation of the liver), changed colour of nails, acne, red
or purple spots, bone fracture, kidney failure, little or no urine
production, waste products in the blood, decreased number
of red blood cells, electrolyte disturbances, defective sperm
formation, menstruation disorders.

------------------------------------------------------------------------------------------------------------------------------------------------------------------------------The following information is intended for medical or healthcare professionals only:
(Continued from overleaf)

hameln

Methotrexate 25 mg/ml solution for injection, pre-filled syringe
Any contact of methotrexate with skin and mucosa is to be
avoided! In case of contamination, the affected parts are to be
rinsed immediately with plenty of water!
For single use only. Any unused solution should be discarded.
Any unused product or waste material should be disposed of
in accordance with local requirements for cytotoxic agents.
Incompatibilities
In the absence of compatibility studies, this medicinal product
must not be mixed with other medicinal products.

Special precautions for storage
Keep the pre-filled syringes in the outer carton in order to
protect from light.
Do not store above 25°C.
Do not refrigerate or freeze.

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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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