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

1. What Ebetrex is and what it is used for

Ebetrex is a drug with the following properties:

  • it prevents the growth of certain cells in the body that are reproduced quickly (anti-tumor drugs)
  • it reduces unwanted reactions in the body’s defense mechanism (immunosuppressive agent) and
  • it has anti-inflammatory effects

Ebetrex is used to treat:

  • active rheumatoid arthritis (RA) in adults
  • polyarticular forms (when five or more joints are affected) of severe, active juvenile idiopathic arthritis (JIA) when treatment with non-steroidal anti-inflammatory drugs ( NSAIDs ) has not given sufficient results.
  • severe therapy-resistant disabling psoriasis, which is not sufficiently improved by other therapies such as light therapy (PUVA) and retinoids, and severe psoriasis affecting the joints (psoriatic arthritis) in adult patients.

Methotrexate contained in Ebetrex may also be approved for the treatment of other conditions not mentioned in this product information. Ask your doctor, pharmacist, or other healthcare professional if you have any further questions, and always follow their instructions.

2. What you need to know before using Ebetrex

If you have any further questions on the use of Ebetrex, ask your doctor or pharmacist.

Do not use Ebetrex:

  • 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 (the doctor decides how severe the disease is)
  • if you have significant liver disease (the doctor decides how severe the disease is)
  • if you have any disorders in the blood formation system
  • if you consume large amounts of alcohol
  • if the function of the body’s own immune system is impaired
  • if you have a severe or active infection, e.g. tuberculosis and HIV
  • if you have ulcers in the gastrointestinal tract (including ulcers in the oral cavity)
  • if you are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and fertility”)
  • if you are being vaccinated with live vaccines at the same time.

Warnings and cautions

Talk to your doctor or pharmacist before using Ebetrex again

  • you have diabetes mellitus which is treated with insulin
  • you have an inactive chronic infection (such as tuberculosis, hepatitis B or C, shingles ( herpes zoster))
  • you have or have had any liver or kidney disease
  • your lung function is impaired
  • you have a pathological accumulation of fluid in the abdominal cavity or the space between the lungs and chest wall ( ascites, pleural effusions)
  • you are dehydrated or suffer from conditions that lead to dehydration (vomiting, diarrhea, stomatitis ).

Acute hemorrhage from the lungs of patients with the underlying rheumatic disease has been reported with methotrexate. If you experience symptoms such as blood in the saliva or bloody cough, contact your doctor immediately.

The treatment should be given once a week.

Improper intake of methotrexate can lead to serious side effects, including potentially fatal ones.

Read section 3 of this leaflet carefully.

If you have previously had skin problems after radiation therapy (radiation-induced dermatitis ) and burns to the skin after sunbathing, these problems may recur during methotrexate treatment (re-reaction).

Children and young people

Dosage instructions depend on the patient’s body weight. Use is not recommended for children <3 years of age due to a lack of experience in this age group.

Children receiving Ebetrex treatment should be monitored particularly closely by specialist physicians so that any side effects can be identified as early as possible.

Older

Elderly people receiving Ebetrex treatment should be monitored particularly closely by a doctor so that any side effects can be identified as early as possible. Dosage one for elderly patients should be relatively low due to age-related impairment of liver and kidney function and low folate reserves.

Skin changes caused by psoriasis may be exacerbated during treatment with Ebetrex with concomitant UV radiation.

Recommended follow-up examinations and precautions:

Even when Ebetrex is used at low doses, serious side effects can occur. For these to be detected early, the doctor must perform checks and laboratory tests.

Before starting treatment :

Before starting treatment, your doctor will check your blood count, kidney function, and liver function. You may have a chest X-ray. Other tests can also be performed during and after treatment. Be sure to come to agreed blood tests.

If the result of any test is abnormal, treatment will not resume until all results are normal again.

Special precautions for treatment with Ebetrex

Methotrexate temporarily affects sperm and egg production, an effect that in most cases decreases after the end of treatment. Methotrexate can cause miscarriage and severe congenital malformations. You must avoid becoming pregnant while using methotrexate and for at least 6 months after stopping treatment. See also the section “Pregnancy, breast-feeding and fertility”.

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 that you are being treated with Ebetrex if you are prescribed another medicine while you are being treated. It is especially important to tell your doctor if you are using:

  • other treatment for rheumatoid arthritis or psoriasis, such as leflunomide, sulfasalazine (also used for ulcerative colitis ), acetylsalicylic acid, phenylbutazone, or amidopyrine
  • alcohol (should be avoided)
  • live vaccines
  • azathioprine (prevents rejection during organ transplants)
  • retinoids (for psoriasis and other skin problems)
  • anticonvulsant drugs (for seizures)
  • cancer treatment
  • barbiturates (sleeping pills)
  • tranquilizer
  • birth control pills
  • probenecid (for gout )
  • antibiotics
  • pyrimethamine (prevention and treatment of malaria )
  • vitamin preparations containing folic acid
  • proton pump inhibitor (for severe heartburn and stomach ulcers )
  • theophylline (for asthma ).

Ebetrex with food, drink, and alcohol

You should not drink any alcohol during treatment with Ebetrex. Avoid drinking too much coffee, caffeinated cold drinks, or black tea. Make sure you drink plenty of fluids during treatment with Ebetrex as dehydration (reduction of body fluids) may increase the harmful effects of Ebetrex.

Pregnancy, breastfeeding, 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.

Pregnancy

Do not use Ebetrex during pregnancy or if you are trying to get pregnant. Methotrexate can cause congenital malformations, birth defects, and miscarriages. It is associated with malformations of the skull, face, heart and blood vessels, brain and arms, and legs. It is therefore very important that methotrexate is not given to pregnant patients or patients planning to become pregnant. Infertile women, pregnancy must be ruled out by appropriate measures, e.g. a pregnancy test before starting treatment.

You must avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment by using reliable contraception during this time (see also the section “Warnings and precautions”).

If you become pregnant during treatment or suspect you may be pregnant, talk to your doctor as soon as possible. You should be offered medical advice on the risk of harmful effects on the child due to the treatment.

If you wish to become pregnant, consult your doctor, who may refer you to specialist advice before the planned start of treatment.

Breast-feeding

Do not breast-feed during treatment as methotrexate passes into breast milk. If your treating doctor considers methotrexate treatment to be necessary during the breastfeeding period, you must stop breast-feeding.

Fertility in men

Available data do not indicate an increased risk of malformations or miscarriages if the father takes less methotrexate than 30 mg/week. However, risk cannot be completely ruled out. Methotrexate may be genotoxic. This means that the drug can cause gene mutation. Methotrexate can affect sperm production and can cause congenital malformations. Therefore, you should avoid getting a woman pregnant and donating sperm while taking methotrexate and for at least 6 months after stopping treatment.

Driving and using machines

Side effects from the central nervous system, such as fatigue and dizziness, may occur during treatment with Ebetrex. Therefore, in some cases, the ability to drive vehicles and/or use machines may be impaired. If you feel tired or dizzy, do not drive or use machines.

You are responsible for assessing whether you are fit to drive a motor vehicle or perform work that requires sharpened attention. One of the factors that can affect your ability in these respects is the use of drugs due to their effects and/or side effects. Descriptions of these effects and side effects can be found in other sections. Read all the information in this leaflet for guidance. If you are not sure, talk to your doctor or pharmacist.

Ebetrex contains sodium chloride and sodium hydroxide

This medicine contains less than 1 mmol (23 mg) sodium per weekly dose, ie essentially ‘sodium-free’.

3. How to use Ebetrex

Important warning regarding the single dose of Ebetrex (methotrexate):

Ebetrex should only be used once a week in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and psoriasis. Using too much Ebetrex (methotrexate) can be life-threatening. Read section 3 of this leaflet very carefully. If you have any further questions on the use of this product, ask your doctor or pharmacist.

Ebetrex should only be prescribed by a doctor with sufficient experience in the drug’s properties and mechanism of action.

Always use this medicine exactly as your doctor or pharmacist has told you. Ask your doctor or pharmacist if you are unsure.

Ebetrex is given only once a week. You will agree with your doctor on a suitable day of the week when you will receive your injection.

Improper intake of Ebetrex can lead to serious side effects, including potentially fatal ones.

The usual dose is:

Patients with rheumatoid arthritis

The recommended starting dose is 7.5 mg methotrexate once a week. Ebetrex is injected as a single dose under the skin, into a muscle, or into a vein (see section “Method of administration and duration of treatment”).

If the effect is still insufficient, the dose of one of Ebetrex may be increased if it is well tolerated. The average weekly dose is 15‑20 mg. In general, a weekly dose of 25 mg should not be exceeded. After the desired treatment goal has been achieved, the dose should, if possible, be reduced to the lowest still effective maintenance dose.

Children and adolescents under 16 years of age with polyarticular forms of juvenile idiopathic arthritis

The recommended dose is 10‑15 mg / m 2 body surface area/week. If the recommended dose is not sufficient, the weekly dose can be increased up to 20 mg / m 2 body surface area/week. However, regular inspections should be carried out more often.

As there are only limited data on intravenous (in a vein) use in children and adolescents, the administration should only be by subcutaneous injection (under the skin) or intramuscularly (in a muscle).

Use is not recommended for children <3 years of age due to a lack of experience in this age group.

Adults with severe forms of psoriasis Vulgaris or psoriatic arthritis

A test dose of 5-10 mg is recommended to evaluate any adverse effects.

This dose can be injected subcutaneously (under the skin), intramuscularly (into a muscle), or intravenously (into a vein).

If no changes in the blood picture have been observed after one week, treatment is continued with approximately 7.5 mg. The dose can be increased gradually (in steps of 5-7.5 mg per week at the same time as monitoring the blood count) until optimal treatment results are achieved. A weekly dose of 20 mg can generally be associated with a significant increase in toxicity. A weekly dose of 30 mg should not be exceeded.

After the desired treatment goal has been achieved, the dose should be reduced weekly, to the lowest still effective maintenance dose.

Patients with renal impairment

For patients with renal impairment, a dose may need to be reduced.

Method of administration and duration of treatment

The attending physician decides how long the treatment should last. Ebetrex is injected once a week! It is recommended that you and your doctor determine a fixed day of the week for injection.

Ebetrex is injected under the skin, into a muscle, or a vein, and must not be given intravenously to children and adolescents.

Treatment with Ebetrex in rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis Vulgaris or psoriatic arthritis is a long-term treatment.

Rheumatoid arthritis

Treatment response can usually be expected 4-8 weeks after starting treatment.

Symptoms may return after stopping treatment with Ebetrex.

Severe forms of psoriasis Vulgaris and psoriatic arthritis ( psoriasis arthropathic)

Treatment response can usually be expected after 2-6 weeks.

Depending on the clinical picture and changes in laboratory values, treatment may then be continued or terminated.

At the beginning of treatment, Ebetrex is injected by healthcare professionals. However, your doctor may decide that it is appropriate for you to learn how to inject Ebetrex under your skin. You will receive appropriate training to be able to do this. Under no circumstances should you try to inject yourself if you have not been trained to do so.

If you use more Ebetrex than you should

Follow your doctor’s dosing recommendations. Do not change the dose on your own.

If you have ingested too much medicine or if e.g. If a child has inadvertently ingested the medicine, contact a doctor, hospital, or the Poison Information Center for risk assessment and advice.

Overdose of methotrexate may cause severe adverse effects. Symptoms of overdose may include bruising or bleeding, abnormal weakness, cold sores, nausea, vomiting, black or bloody stools, bloody coughs or vomiting similar to coffee grounds, and decreased urination. See also section 4.

Take the medicine pack with you if you see a doctor or hospital.

The antidote for an overdose is calcium folinate.

If you forget to use Ebetrex

Do not take a double dose to make up for a forgotten dose, but continue to take your prescribed dose. Ask your doctor for advice.

If you stop using Ebetrex

You should not stop or stop taking Ebetrex unless you have discussed it with your doctor. Contact a doctor immediately if you suspect serious side effects.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately if you experience sudden wheezing, difficulty breathing, swelling of the eyelids, face, or lips, rash or itching (especially if it affects the whole body), and fainting (this may be a sign of severe allergic reactions or anaphylactic shock ).

Serious side effects are

If any of the following side effects occur, contact your doctor immediately:

  • lung problems (with symptoms such as general malaise, dry cough, shortness of breath, shortness of breath at rest, chest pain, or fever)
  • blood in saliva or cough
  • severe blisters or flaky skin (this may also affect the mouth, eyes, or genitals)
  • abnormal bleeding (including bloody vomiting) or bruising
  • severe diarrhea
  • cold sores
  • black or tar-like stools
  • blood in the urine or feces
  • pin-sized red dots on the skin
  • fever
  • yellowing of the skin (jaundice)
  • difficult or painful to urinate
  • swelling of the hands, ankles, or feet or changes in how often you need to urinate or a decrease or lack of urine (signs of kidney failure )
  • thirst and/or frequent urination
  • cramps
  • unconsciousness
  • blurred vision or impaired vision.

The following side effects have also been reported:

Very common (may affect more than 1 user in 10):

  • loss of appetite, nausea, vomiting, abdominal pain
  • inflammation and sores in the mouth and throat
  • increase in liver enzymes.

Common (may affect up to 1 in 10 people):

  • reduced blood cell formation with decreased number of white and/or red blood cells and/or platelets ( leukopenia, anemia, thrombocytopenia )
  • headache
  • fatigue, drowsiness
  • irritating, tingling, stinging, or burning sensation in the skin, rash, reddening of the skin, itching
  • pneumonia ( Pneumonitis )
  • diarrhea.

Uncommon (may affect up to 1 in 100 people):

  • shingles ( herpes zoster)
  • lymphoma (a type of lymph node cancer) (which spontaneously recurred in several patients as soon as treatment with Ebetrex was stopped)
  • reduction in the number of blood cells and platelets
  • severe allergic reactions
  • diabetes
  • Depression
  • weakness in the entire left or right half of the body
  • dizziness, confusion
  • cramps
  • brain damage (leukoencephalopathy/encephalopathy)
  • inflammation of blood vessels
  • lung damage, water around the lungs
  • ulcers and bleeding in the gastrointestinal tract
  • inflammation of the pancreas
  • liver problem
  • decreasing blood proteins
  • hives (only), photosensitivity, tanning of the skin
  • severe toxic skin reactions including blistering and loosening of the upper layer of the skin ( Stevens-Johnson syndrome, Lyell’s syndrome )
  • hair loss
  • increase in rheumatic nodules (lumps under the skin)
  • painful psoriasis
  • joint or muscle pain
  • osteoporosis (decreased bone mass)
  • inflammation and ulcers in the bladder, (possibly with blood in the urine), painful urination
  • fetal malformations
  • inflammation and ulcers in the vagina
  • burning sensation or tissue damage after injection of Ebetrex into the muscle.

Rare (may affect up to 1 in 1,000 people):

  • sepsis (blood poisoning)
  • very large red blood cells (megaloblastic anemia )
  • Mood swings
  • temporary problems with perception (sensory impressions)
  • the weakening of well-controlled movements throughout the body
  • trouble speaking
  • serious eye problems
  • low blood pressure
  • blood clots
  • sore throat
  • respiratory arrest
  • inflammation of the gastrointestinal tract, bloody stools
  • inflammation of the gums
  • acute hepatitis (inflammation of the liver)
  • discoloration of the nails, nail detachment
  • acne, red or purple spots on the skin caused by bleeding from blood vessels
  • bone fracture due to exertion
  • electrolyte disturbances
  • miscarriage
  • defective sperm formation
  • menstrual disorders.

Very rare (may affect up to 1 in 10,000 people):

  • cold sores ( herpes simplex)
  • hepatitis ( inflammation of the liver)
  • severe bone marrow failure
  • immunodeficiency ( hypogammaglobulinemia )
  • pain
  • muscle weakness
  • taste changes (metallic taste)
  • inflammation of the meninges leading to paralysis or vomiting
  • Red eyes
  • inflammation of the sac around the heart, fluid in the sac around the heart
  • pneumonia, difficulty breathing, asthma
  • vomiting blood
  • liver failure
  • infection around a fingernail, boils, small blood vessels in the skin
  • protein in the urine
  • fetal death
  • problems forming eggs (women) and sperm (men)
  • decreased sex drive
  • problems getting an erection
  • discharge from the vagina
  • infertility
  • mild local skin reactions if Ebetrex is given under the skin
  • lymphoproliferative disorders (abnormal growth of white blood cells )
  • the feeling of numbness or crawling / lower sensitivity to stimulation than normal.

Has been reported (occurs in an unknown number of users):

  • the infection you which in some cases can be fatal
  • swollen lymph nodes
  • the immune system is not working properly
  • fever
  • inflammation of small blood vessels caused by an allergic reaction
  • inflammation of the gastric mucosa
  • slow wound healing
  • bleeding from the lungs
  • bone damage in the jaw (as a result of abnormal growth of white blood cells )
  • tissue destruction at the injection site
  • reddening of the skin and scaly skin
  • swelling.

When methotrexate is given intramuscularly, it is common for local side effects(burning sensation) or damage (formation of a sterile abscess, destruction of adipose tissue) to occur at the injection site.

Subcutaneous application of methotrexate is well tolerated locally. Only mild skin reactions have been observed, which subside during the course of treatment.

Methotrexate may cause a decrease in the number of white blood cells and your resistance to infection may be weakened. If you get an infection with symptoms such as fever and severe deterioration of your general condition, or fever with local infection symptoms such as sore throat / sore throat/pain in the mouth, or problems with urination, you should contact your doctor immediately. Your doctor will take a blood test to check for a possible decrease in white blood cell count ( agranulocytosis). You must tell your doctor about your medicine.

Methotrexate can cause serious (sometimes life-threatening) side effects. Therefore, your doctor will perform tests to check if there is anything abnormal in your blood (eg low white blood cell count, low platelet count, lymphoma ) and changes in your kidneys or liver.

Reporting of side effects

5. How to store Ebetrex

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label on the pre-filled syringe and the carton after EXP. The expiration date is the last day of the specified month.

Store in the original package. Sensitive to light.

Do not store above 25 ° C.

Must be used immediately after opening.

Do not use Ebetrex if the solution is not clear or contains particles.

For single use only. Unused solutions should be discarded.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Contents of the packaging and other information

Content declaration

The active substance is methotrexate.

1 ml solution for injection contains 20 mg methotrexate (as 21.94 mg 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 the medicine looks like and the contents of the pack

Ebetrex solution for injection is supplied in pre-filled syringes as a clear, yellowish solution for injection.

Each carton contains 1 pre-filled syringe 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, or 1.5 ml solution for injection, disposable injection needles with or without safety needle, and alcohol swabs.

Multiple packs contain 4, 5, 6, 1,2, or 30 pre-filled syringes (1 pre-filled syringe per carton).

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

EBEWE Pharma Ges.mbH Nfg.KG, Mondseestrasse 11, 4866 Unterach, Austria

Agent

Sandoz A / S, Edvard Thomsens Vej 14, 2300 Copenhagen S, Denmark

Muhammad Nadeem

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