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EBETREX 20 MG/ML SOLUTION FOR INJECTION PRE-FILLED SYRINGE

Active substance(s): METHOTREXATE

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PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

Ebetrex 20 mg/ml solution for injection, pre-filled syringe
Methotrexate

Read all of this leaflet carefully before you start using this medicine.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or your pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
In this leaflet:
1. What Ebetrex is and what it is used for
2. Before you use Ebetrex
3. How to use Ebetrex
4. Possible side effects
5. How to store Ebetrex
6. Further information
1. WHAT EBETREX IS AND WHAT IT IS USED FOR
Ebetrex 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
Ebetrex is used in patients with:
- Active rheumatoid arthritis (RA) in adult patients
- Polyarthritic forms (when five or more joints are involved) of severe, active, juvenile idiopathic arthritis (JIA) when the response to non-steroidal 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 psoriasis affecting
the joints (psoriatic arthritis) in adult patients.
2. BEFORE YOU USE EBETREX
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.
Faulty dosing of methotrexate may lead to serious adverse effects including fatal course. Please read section 3 of this PL very carefully.
Please ask your doctor or pharmacist before using Ebetrex if you have any question.
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Take special care with Ebetrex if you
- have diabetes mellitus treated with insulin
- have inactive, prolonged infections (e.g. tuberculosis, hepatitis B or C, shingles (herpes zoster))
- have/had any liver or kidney disease
- have problem with your lung function
- have abnormal accumulation of liquid in the abdomen or in the cavity between the lungs and chest wall (ascites, pleural effusions)
- 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 have experienced problems with your skin after radiation therapy (radiation induced dermatitis) and sun-burn these conditions can reappear under methotrexate therapy (recallreaction).
Use in children, adolescents and elderly
Dose instructions depend on patient’s body weight. Use in children < 3 years of age is not recommended due to the insufficient experience in this age group.
Children and the elderly under Ebetrex treatment should be kept under particularly close, medical surveillance by specialists in this area in order to identify possible side effects as
early as possible.
Dose for elderly patients should be relatively low due to age-related reduced liver and kidney function and low folate reserves.
Skin changes caused by psoriasis can worsen during treatment with Ebetrex if exposure to UV irradiation occurs at the same time.
Recommended follow-up examinations and precautions:
Even when Ebetrex is used at low doses, serious side effects can occur. In order to recognise these in good time, your doctor must carry out check-ups and laboratory tests.
Before the start of treatment:
Before treatment is started your doctor may carry out blood tests, and also to 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.



















not use Ebetrex if you
are allergic (hypersensitive) to methotrexate or to any of the other ingredients of Ebetrex
have significant kidney disease (your doctor decides the severity of the disease)
have significant liver disease (your doctor decides the severity of your disease)
have disorders of the blood-forming system
your alcohol consumption is high
have an impaired immune system
have a severe or existing infection, e.g. tuberculosis and HIV
have gastrointestinal ulcers (including ulcers in oral cavity)
are pregnant or breast-feeding (see section “Pregnancy and lactation”)
receive vaccinations with live vaccines at the same time.

Using other medicines
Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Remember to tell your doctor about your treatment with Ebetrex, 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, sulphasalazine (also used for ulcerative colitis), aspirin, phenylbutazone, or amidopyrine
- alcohol (should be avoided)
- live vaccinations
- azathioprine (used to prevent rejection after an organ transplant)
- retinoids (used to treat psoriasis and other skin disorders)
- anticonvulsant drugs (prevent fits)
- cancer treatments
- barbiturates (sleeping injection)
- tranquillisers
- oral contraceptives
- probenecid (against 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)





Using Ebetrex with food and drink
During treatment with Ebetrex , you should not drink any alcohol and you should avoid excessive consumption of coffee, , soft drinks containing caffeine and black tea.
Also make sure you drink plenty of liquids during treatment with Ebetrex because dehydration (reduction in body water) can increase the toxicity of Ebetrex.





Pregnancy and breast-feeding
Pregnancy
Do not use Ebetrex 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 child-bearing 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.
It should be considered that the optimal time interval between the end of the methotrexate treatment of one partner and pregnancy is not exactly known. Talk to your doctor for further
advice.
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 cause genetic mutation.
Breast-feeding
Do not breast-feed during treatment, because methotrexate passes into breast milk. If your attending doctor considers treatment with methotrexate absolutely necessary during the
lactation period, you must stop breast-feeding.
Male fertility
Methotrexate may be genotoxic. This means that the medicine may cause genetic mutation. Methotrexate can affect sperm and egg 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. It should be considered that the optimal time
interval between the end of the methotrexate treatment of one partner and pregnancy is not exactly known. Talk to your doctor for further advice. 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.














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Driving and using machines
Side effects affecting the central nervous system, such as tiredness and dizziness, may occur during treatment with Ebetrex. In some cases, the ability to drive vehicles and/or use
machines may therefore be impaired. If you feel tired or dizzy, you should not drive or use machines.
Important information about some of the ingredients of sodium
This medicinal product contains less than 1 mmol (23 mg) sodium per weekly dose, i.e. essentially ‘sodium- free’.
HOW TO USE EBETREX
Ebetrex should only be prescribed by physicians who are familiar with the various characteristics of the medicinal products and its mode of action.
Always use this medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are unsure.
Ebetrex is administered once a week only. Together with your doctor you decide on a suitable weekday each week on which you receive your injection.
Incorrect intake of Ebetrex can lead to severe, including potentially lethal, side effects.
The usual dose is:
Dose in patients with rheumatoid arthritis
The recommended starting dose for methotrexate is 7.5 mg once a week. Ebetrex is given in a single application as injection under the skin, into a muscle or a vein (see section
“Method and duration of administration”).
In case of inadequate action and if tolerated well, Ebetrex doses may be increased. The mean weekly dose is 15-20 mg. Generally, a weekly dose of 25 mg Ebetrex should not be
exceeded. Upon achieving desired therapeutic results, the dose should – if possible – be gradually reduced to the lowest possible effective maintenance dose.
Dose 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 per week. In cases with inadequate response, the weekly dose may be increased up to 20 mg/m2 body surface area/week.
However, regular check-ups should be done more often. As there is very little data about giving the drug intravenously (into a vein) in children and adolescents, it should only be given
by subcutaneous (under the skin) or intramuscular (into the muscle) injection.
Use in children < 3 years of age is not recommended due to the insufficient experience in this age group.
Adults with severe forms of psoriasis vulgaris or psoriatic arthritis
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), intramuscularly (into a muscle) or intravenously (into a vein).
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 20 mg can be associated with significant increase in toxicity. A dose
of 30 mg per week should not be exceeded.
Upon achieving desired therapeutic results, the dose should be weekly reduced to the lowest possible effective maintenance dose for the individual patient.
Patients with a kidney disorder
Patients with a kidney disorder may need a reduced dose.
Method and duration of administration
The duration of the treatment is determined by the treating physician. Ebetrex is injected once weekly! It is recommended to specify a certain day of the week as “day for injection”.
Ebetrex is given as injection under the skin, into a muscle or a vein, in children and adolescents it must not be given intravenously.
Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris and psoriatic arthritis with Ebetrex 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 Ebetrex discontinuation.
Severe types of psoriasis vulgaris and psoriatic arthritis (psoriasis arthropatica)
Response to treatment can generally be expected after 2-6 weeks. Depending on the clinical picture and the changes of laboratory parameters, the therapy is then continued or
discontinued.
At the start of your therapy, Ebetrex may be injected by medical staff. However, your doctor may decide that it is right for you to learn how to inject Ebetrex under the skin 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.
If you use more Ebetrex than you should
Follow the dose recommendations of your treating doctor. Do not change the dose of your own accord.
If you suspect that you (or someone else) have used too much Ebetrex, please tell your doctor or contact the nearest hospital casualty department immediately. He/she will decide
on any necessary treatment measures, depending on the severity of intoxication.
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 4.




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 Ebetrex
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 Ebetrex
You should not interrupt or discontinue Ebetrex treatment, 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 medicine, ask your doctor or pharmacist.


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POSSIBLE SIDE EFFECTS
Like all medicines, this medicine 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
• black or tarry stools
• blood in the urine or stools
• tiny red spots on the skin
• fever
• yellowing of the skin (jaundice)
• pain or difficulty in passing urine
• thirst and/or frequent urination
• fits (convulsions)
• loss of consciousness
• blurred or decreased vision
The following side effects have also been reported:
very common:

may affect more than 1 in 10 people

common:

may affect up to 1 in 10 people

uncommon:

may affect up to 1 in 100 people

rare:

may affect up to 1 in 1,000 people

very rare:

may affect up to 1 in 10,000 people

not known:

frequency cannot be estimated from the available data

Very common:
• loss of appetite, nausea (feeling sick), vomiting, tummy pain
• inflammation and ulcers in the mouth and throat
• increase in liver enzymes
Common:
• reduced blood cell formation with decrease in white and/or red blood cells and/or platelets (leukopenia, anaemia, thrombocytopenia)
• headache
• tiredness, drowsiness
• tingling, tickling, pricking or burning of the skin, rash, reddening of the skin, itching
• inflammation of the lungs (pneumonitis)
• diarrhoea
Uncommon:
• shingles (herpes zoster)
• lymphoma (which spontaneously regressed in a number of cases as soon as Ebetrex was stopped)
• decrease in the number of blood cells and platelets
• severe allergic reactions
• diabetes

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• depression
• weakness of the entire left or right side of the body
• dizziness, confusion
• fits
• damage of the brain (leukoencephalopathy/encephalopathy), inflammation of blood vessels
• lung damage, water around the lungs
• ulcers and bleeding in the digestive tract
• inflammation of the pancreas
• liver disorders
• decreased blood protein
• nettle rash (alone), light sensitivity, brown skin
• severe toxic skin reactions including bladder formation and detachment of the top layer of the skin (Stevens-Johnson syndrome, Lyell’s syndrome)
• hair loss
• increase of rheumatic nodules
• painful psoriasis
• joint or muscle pain
• osteoporosis (reduction of bone mass)
• inflammation and ulcers of the bladder (possibly with blood in the urine), painful urination
• malformations in the unborn child
• inflammation and ulcers of the vagina
• burning sensation or damage of tissue after injection of Ebetrex in the muscle.
Rare:
• sepsis
• very large red blood cells (megaloblastic anaemia)
• mood fluctuations
• temporary problems with perception
• weakness of voluntary movement in the whole body
• problems with speaking
• severe problems with your eyes
• low blood pressure
• blood clots
• sore throat
• interruption of breathing
• inflammation of the digestive tract, bloody stools
• inflamed gums
• acute hepatitis (inflammation of the liver)
• changed colour of nails, loss of nails
• acne, red or purple spots due to vessel bleeding
• bone fracture due to exertion
• electrolyte disturbances
• abortion
• defective sperm formation
• menstruation disorders.
Very rare:
• cold sores (herpes simplex)
• hepatitis
• severe failure of the bone marrow
• immune deficiency (hypogammaglobulinaemia)
• pain
• muscle weakness
• changes in sense of taste (metallic taste)
• inflammation of the lining of the brain causing paralysis or vomiting
• red eyes
• inflammation of the sac around the heart, fluid in the sac around the heart
• pneumonia, breathing problems, asthma
• vomiting blood
• liver failure
• infection around a fingernail, boils, small blood vessels in the skin
• protein in the urine
• death of the unborn child
• problems in the formation of eggs (women) and sperm (men)
• loss of sex drive
• problems having an erection
• vaginal discharge
• infertility
• mild local skin reactions if Ebetrex is administered under the skin.
Not known (frequency cannot be estimated from the available data)
• infections which may be fatal in some cases
• swelling of lymph nodes
• cancer of the blood forming system, e.g lymphoma, leukemia (first signs could be fever, sore throat, ulcers in your mouth, strong exhaustion, nose bleed and bruises)
• immune system not working properly
• fever
• inflammation of small blood vessels caused by an allergic reaction
• inflammation of the lining of the abdomen
• slow wound healing.
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.
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). It 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.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
HOW TO STORE EBETREX
Keep out of the reach and sight of children.
Do not use this medicine 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.
Store in the original package in order to protect from light.
Do not store above 25°C.
The product has to be used immediately after opening.
You must not use Ebetrex, if the solution is not clear and contains particles.
For single use only. Any unused solution should be discarded!
This medicine and its packaging must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines or packaging no longer required.
These measures will help to protect the environment.

6. FURTHER INFORMATION















What Ebetrex contains:
The active substance is: Methotrexate.
1 ml of solution for injection contains 20 mg methotrexate (as 21.94mg methotrexate disodium).
1 pre-filled syringe with 0.375 ml solution for injection contains 7.5 mg methotrexate.
1 pre-filled syringe with 0.5 ml solution for injection contains 10 mg methotrexate.
1 pre-filled syringe with 0.625 ml solution for injection contains 12.5 mg methotrexate.
1 pre-filled syringe with 0.75 ml solution for injection contains 15 mg methotrexate.
1 pre-filled syringe with 0.875 ml solution for injection contains 17.5 mg methotrexate.
1 pre-filled syringe with 1 ml solution for injection contains 20 mg methotrexate.
1 pre-filled syringe with 1.125 ml solution for injection contains 22.5 mg methotrexate.
1 pre-filled syringe with 1.25 ml solution for injection contains 25 mg methotrexate.
1 pre-filled syringe with 1.375 ml solution for injection contains 27.5 mg methotrexate.
1 pre-filled syringe with 1.5 ml solution for injection contains 30 mg methotrexate.
The other ingredients are: sodium chloride, sodium hydroxide for pH adjustment and water for injections.





What Ebetrex looks like and contents of the pack:
Ebetrex is solution for injection available in pre-filled syringes as a clear, yellowish solution for injection.
Each box contains 1, 4, 5, 6, 12 or 30 pre-filled syringes with 0.375 ml, 0.5 ml, 0.625 ml, 0.75 ml, 0.875 ml, 1 ml, 1.125 ml, 1.25 ml, 1.375 ml and 1.5 ml solution for injection, singleuse injection needles without or with security canula and alcohol pads.
Not all pack sizes may be marketed.







Marketing Authorization Holder and Manufacturer:
EBEWE Pharma Ges.m.b.H Nfg. KG
Mondseestraße 11
4866 Unterach
Austria



This leaflet was last revised on 07/2015.



The following information is intended for healthcare professionals only:



Ebetrex 20 mg/ml solution for injection, pre-filled syringe







Instructions for use and handling and disposal
The solutions should be clear and without particles
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 Ebetrex.
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
Store in the original package in order to protect from light.
Do not store above 25°C
Step-by-step instructions for subcutaneous injection:
• Open the box and read the package leaflet carefully.
• Take out the inner-package, containing the pre-filled syringe and cannula package
• Open the inner-package by pulling the corner flap.,– Take out the pre-filled syringe.
• Remove (twist) the grey rubber cap from the syringe, without touching the opening
of the pre-filled syringe.




• Pull the Case straight-off from the needle. Check the visual indication.
Do not touch the Shield

• Place the syringe back into the inner-package. The yellow solution will be unable to escape.

• With two fingers, form a skin fold and without hesitation and in one continuous
motion, puncture it almost vertically. Push the needle completely into the skin
fold until the shield is completely retracted.

• Verify first that the tamper-evident label is undamaged.

• Remove the cap as illustrated

• Then, while maintaining constant pressure against the skin, slowly push the
plunger down and inject all the fluid underneath the skin.

• Attach the needle, with its Case, onto the syringe and fix it by twisting.
• After injection,the visual indicator will disappear confirming that the shielding
mechanism is automatically locked; the needle shield is locked and protects
against sharp injuries.

• Choose an injection site. Wipe the injection site with the alcohol pad, using a circular motion.
Do not touch this area before injecting.
• Dab the injection site with a swab. Do not rub, as this will cause irritation at
the injection site.



ak43yoth.indd 3

The syringe and needle should be disposed of following local procedures and
regulations (in a sharps container)

30.07.2015 11:34:42

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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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