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EBETREX 10MG/ML SOLUTION FOR INJECTION PRE-FILLED SYRINGE

Active substance(s): METHOTREXATE

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Package leaflet: Information for the user

Ebetrex 10mg/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, please ask your doctor or your pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their sign 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 Ebetrexat is and what it is used for
2. What you need to know before you use Ebetrexat
3. How to use Ebetrexat
4. Possible side effects
5. How to store Ebetrexat
6. Contents of the pack and other information
1. WHAT EBETREXAT 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. WHAT YOU NEED TO KNOW 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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Warning and precautions
Talk to your doctor or pharmacist before using 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
- are severely overweight
- 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
(recall-reaction).
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, 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.






















not use Ebetrex if you
are allergic to methotrexate or any the other ingredients of this medicine (listed in section 6)
have significant kidney disease (or doctor decides the severity of the disease)
you 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
are pregnant or breast-feeding (see section “Pregnancy and lactation”)
receive vaccinations with live vaccines at the same time.

Special precautionary measures during treatment of Ebetrex
Ebetrex should only be prescribed by doctors with sufficient experience in the Ebetrex 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 and lactation”.
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.
Other medicines and Ebetrex
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)





Ebetrex with food, drink and alcohol
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, breast-feeding and fertility
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 (see also section “Take special care with Ebetrex”).
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. 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 (see also section “Warning and precautions”).
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.










ASAASSSASS




Ebetrexat contains sodium
This medicinal product contains less than 1 mmol (23 mg) sodium per weekly dose, i.e. essentially ‘sodium- free’.

3.








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 Ebetrex exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
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 recommended 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.











Use in children and adolescents
Dose 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 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).



The following information is intended for medical or healthcare professionals only:







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.
Do not freeze.

ASAASSSASS



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.

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

• Now, open the cannula packaging by pulling the flap. Do not touch the round sterile opening. To avoid this, keep hold of the bottom end of the cannula packaging.

• Attach the cannula, with its packaging, onto the syringe and fix it (clockwise). Put the syringe in a readily accessible place.

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ASAASSSASS



















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 30 mg 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
• Brain disorder
The following side effects have also been reported:
Very common:
Loss of appetite, nausea (feeling sick), vomiting, tummy pain, inflammation and ulcers in the mouth and throat, and increase in liver enzymes
Common: may affect more than 1 in 10 people
Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets (leukopenia, anaemia, thrombocytopenia), headache, tiredness, drowsiness, inflammation
of the lungs (pneumonia) with dry, non-productive cough, shortness of breath and fever, diarrhoea, rash, reddening of the skin, itching.
Uncommon: may affect up to 1 in 100 people
Decrease in the number of blood cells and platelets , dizziness, confusion, depression, fits, inflammation of blood vessels, lung damage, ulcers and bleeding in the digestive
tract, liver disorders, diabetes, decreased blood protein, nettle rash (alone), light sensitivity, brown skin, hair loss, increase of rheumatic nodules, shingles, 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, severe allergic reactions,
inflammation and ulcers of the vagina, slow wound healing.
Rare: may affect up to 1 in 1,000 people
Inflammation of the sac around the heart, fluid in the sac around the heart, severe visual disturbance, mood fluctuations, 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 due to vessel bleeding, bone fracture, kidney failure, decrease or absence of urine, electrolyte disturbances, defective sperm formation, menstruation
disorders.
Very rare: may affect up to 1 in 10,000 people
Infections, severe failure of the bone marrow, liver failure, swollen glands, sleeplessness, pain, muscle weakness, pins and needles, 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 in the lungs, vomiting blood, cold sores, protein in the urine,
fever, 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, vaginal discharge, infertility, male breast enlargement (gynaecomastia).
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 you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet.

5. HOW TO STORE EBETREX
Keep out of the sight and reach of children.
Do not use this medicinal product 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 in the original package in order to protect from light.
Do not store above 25°C. Do not freeze.
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!
Do not throw away any medicine and its packaging 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 Ebetrex contains
The active substance is methotrexate.
1 ml solution for injection contains 10 mg methotrexate (as 10.97 mg methotrexate disodium).
1 pre-filled syringe with 0.75 ml solution for injection contains 7.5 mg methotrexate.
1 pre-filled syringe with 1 ml solution for injection contains 10 mg methotrexate.
1 pre-filled syringe with 1.5 ml solution for injection contains 15 mg methotrexate.
1 pre-filled syringe with 2 ml solution for injection contains 20 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 pre-filled syringes contain a clear, yellow solution for injection.
Each box contains 1, 4 or 5 pre-filled syringes with 0.75 ml, 1.0 ml, 1.5 ml and 2.0 ml solution for injection, single-use injection needles and alcohol pads.
Not all pack sizes may be marketed.




Marketing Authorisation Holder and Manufacturer
EBEWE Pharma Ges.m.b.H. Nfg.KG, A-4866 Unterach, Austria



This leaflet was last revised in 10/2013.

• Choose an injection site. Wipe the injection site with the alcohol pad, using a circular motion. Do not touch this area before injecting.

• Pull the packaging from the cannula. Put aside the cannula packaging.

• Do not touch the sterile cannula. If this should happen, ask your doctor or pharmacist about using of another cannula. With two fingers, form a skin fold and puncture it almost
vertically.

• Push the cannula completely into the skin fold. Then, slowly push the plunger down and inject all the fluid underneath the skin.

• Carefully remove the cannula and dab the injection site with a swab. Do not rub, as this will cause irritation at the injection site.

• To avoid any injuries dispose the used syringes in a sharps bin.

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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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