Patient leaflet - Ebetrex 10 mg / ml solution for injection Pre-filled syringe

1. What Ebetrex is and what it is used for

Ebetrex is a medicine containing methotrexate. Methotrexate is a substance 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 (children > 3 years) 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

Please ask your doctor or pharmacist before using Ebetrex if you have any questions.

Do not use Ebetrex if you

are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6)
have a severe or existing infection
have inflammation in your mouth or active gastrointestinal ulcers
have significant kidney disease (your 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 doctor decides the severity of your disease)
your alcohol consumption is high, if you have a liver disease caused by alcohol or other chronic liver disease
have an impaired immune system (e.g. AIDS)
are pregnant or breast-feeding (see section “Pregnancy and lactation”)

Warning and precautions

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.

Always use Ebetrex exactly as your doctor has told you.

Incorrect dosing of methotrexate can lead to serious side effects including fatal course. Read section 3 of this package leaflet carefully.

Talk to your doctor or pharmacist before using Ebetrex.

Especially in the elderly, deaths were reported following the accidental daily use of the weekly dose.

Methotrexate should only be prescribed by physicians who have sufficient experience in treating the disease with methotrexate.

Your doctor will inform you about the possible benefit and the risks (including early signs and symptoms of toxicity) of methotrexate therapy.

You need to be closely monitored during therapy so that signs of possible toxic effects or adverse reactions may be detected with minimal delay.

If you notice symptoms of intoxication (please refer to section 4 “Possible side effects”), contact your doctor immediately. Your doctor will decide on the subsequently necessary monitoring and treatment of the signs of intoxication and informs you about further measures.

Talk to your doctor 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), since these diseases might be reactivated
have/had any liver or kidney disease
have/had problems with your lung function
are obese
have abnormal accumulation of liquid in the abdomen or in the cavity between the lungs and chest wall (ascites, pleural effusions)

Liver function

Methotrexate can damage the liver, during treatment with Ebetrex you should avoid drinking alcohol and taking other medicines which might damage the liver. Before and during treatment with Ebetrex your doctor should carry out blood tests to monitor your liver function. Please also refer to section “Ebetrex and other medicines”, “Ebetrex with food, drink and alcohol” and section 4.

Kidney function

Ebetrex can damage your kidneys. Your doctor should carry out blood tests before and during therapy to monitor your kidney function. If you are dehydrated or suffer from conditions leading to dehydration (vomiting, diarrhoea, stomatitis) the toxicity of methotrexate might increase. Your doctor might stop therapy with Ebetrex. Please also refer to section 4.

Blood-forming system and immune system

Treatment with Ebetrex might damage your bone marrow (bone marrow depression). This might lead to infections and/or severe bleeding and anaemia.

Your doctor will carry out blood tests so these can be treated as early as possible.

Please contact your doctor if you experience fever, sore throat, ulcers in your mouth, flu-like symptoms, exhaustion, bruises or bleeding.

Methotrexate can influence the efficacy of vaccinations or tests for immune reactivity due to its effect on the immune system.

Nervous system

Certain brain disorders (encephalitis/encephalopathy) which might be fatal have been reported with methotrexate given intravenously. There have been reports on leukoencephalopathy in patients treated with oral methotrexate. If you, your partner or your caregiver notice new onset or worsening of neurological symptoms including general muscle weakness, disturbance of vision, changes in thinking, memory and orientation leading to confusion and personality changes contact your doctor immediately because these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

Skin

Methotrexate can make your skin sensitive to sunlight, so you should avoid extended sun exposure and not use a sun-lamp or sun-bed. Before you go out in the sun, use a sunprotection product with a high protection factor. Always wear a hat and clothes which cover your arms and legs.

You should also not visit a tanning salon without clarifying with your doctor first.

Skin changes caused by psoriasis can worsen during treatment with Ebetrex if exposure to UV irradiation occurs at the same time.

If you have experienced problems with your skin after radiation therapy (radiation-induced dermatitis) and sunburn these conditions can reappear under methotrexate therapy (recall-reaction).

There have been reports about serious, sometimes fatal skin reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome) after single or continuous use of methotrexate (please refer to section 4).

Treatment with methotrexate might lead to serious complications in your gastrointestinal system. In that case, treatment with methotrexate has to be stopped.

Please contact your doctor immediately if you experience any problems in your gastrointestinal system (please refer to section 4).

Infections

Treatment with methotrexate might lead to infections, which can be fatal in some cases.

Please contact your doctor immediately if you experience signs of infection (please refer to section 4).

Lung function

Treatment with methotrexate might lead to serious lung complications. In that case, treatment with methotrexate has to be stopped.

Please contact your doctor immediately if you experience any breathing problems or problems with your lungs (please refer to section 4).

Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. If you experience symptoms of spitting or coughing up blood, you should contact your doctor immediately.

Tumours

Uncommonly cancer in the lymph nodes (malign lymphoma) may occur in patients receiving low dose methotrexate, which in some cases alleviated after therapy has been stopped; therefore, no cytotoxic treatment was required. If lymphomas occur, methotrexate therapy should be stopped first, and only if the lymphoma does not recede, appropriate cytostatic therapy should be initiated.

Methotrexate temporarily affects sperm and egg production, which is reversible in most cases

Methotrexate can cause miscarriage and severe birth defects. You must avoid becoming pregnant when using methotrexate and for at least six months after treatment has stopped if you are a woman. If you are a man you should avoid fathering a child if you are being given methotrexate at the time and for at least 3 months after the end of your treatment. See also section “Pregnancy, breast-feeding and fertility”.

Recommended follow-up examinations and precautions:

Even if Ebetrex is used at low doses, serious side effects can occur. In order to detect them in time, your doctor must perform monitoring examinations and laboratory tests.

Before the start of treatment:

Before you start treatment, your blood will be checked to see if you have enough blood cells. Your blood will also be tested to check your liver function and to find out if you have hepatitis. Furthermore, serum albumin (a protein in the blood), hepatitis (liver infection) status and kidney function will be checked. The doctor may also decide to run other liver tests, some of these may be images of your liver and others may need a small sample of tissue taken from the liver in order to examine it more closely. Your doctor may also check to see if you have tuberculosis and they may X-ray your chest or perform a lung function test.

During the treatment:

Your doctor may perform the following examinations:

-examination of the oral cavity and the pharynx for changes in the mucous membrane such as inflammation or ulceration

-blood tests/ blood count with number of blood cells and measurement of serum methotrexate levels

-blood test to monitor liver function

-Imaging tests to monitor liver condition

small sample of tissue taken from the liver in order to examine it more closely
blood test to monitor kidney function
respiratory tract monitoring and, if necessary, lung function test

It is very important that you appear for these scheduled examinations.

If the results of any of these tests are conspicuous, your doctor will adjust your treatment accordingly.

Do not miss appointments for any tests.

If the results of any of these tests are abnormal, your doctor will take the appropriate measures.

Elderly patients

Elderly patients under treatment with methotrexate should be monitored closely by a physician so that possible side effects can be detected as early as possible.

Age-related impairment of liver and kidney function as well as low body reserves of the vitamin folic acid in old age require a relatively low dosage of methotrexate.

Children and adolescents

Use in children < 3 years of age is not recommended due to the insufficient experience in this age group.

Children treated with methotrexate should be kept under particularly close medical surveillance by specialists in this area in order to identify possible side effects as early as possible.

Other medicines and Ebetrex

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines including medicines without a prescription like herbal remedies or vitamins.

It is especially important to tell your doctor if you are using:

Medicines which might damage the liver like:
- Azathioprine (used to prevent rejection after an organ transplant)
- Leflunomide (for rheumatoid arthritis)
- Retinoids (used to treat psoriasis and other skin disorders)
- Sulfasalazine (used for rheumatoid arthritis and ulcerative colitis)
other treatments for rheumatoid arthritis or psoriasis such as gold, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, and ciclosporin (for supressing the immune system)
Medicines for treatment of pain and/or inflammation (non-steroidal anti-inflammatory drugs or salicylates such as ibuprofen, indomethacin, phenylbutazone, amidopyridine derivates and acetylsalicylic acid including salicylic acid). This is also applicable for medicines available without a prescription.
Certain cancer treatments (cytotoxics like doxorubicin, mercaptopurine, procarbazine, cisplatin, L-asparaginase, vincristine, cytarabine and 5-fluorouracil)
antibiotics (e.g. penicillin, sulphonamides, trimethoprim/sulfamethoxazol, tetracyclines, ciprofloxacin, pristinamycin, chloramphenicol)
tranquilisers (e.g. benzodiazepines like lorazepam, alprazolam)
medicines for increased blood glucose levels (tolbutamide, glipizide, glimepiride)
para-aminobenzoic acid (treatment of skin disorders)
oral contraceptives
triamterene (treatment of high blood pressure)
anticonvulsant medicines like phenytoin, levetiracetam (prevents fits) and barbiturates (also used as sleeping injection)
probenecid (against gout)
aminohippuric acid (substance to check renal function)
pyrimethamine (used to prevent and treat malaria)
drugs used to treat severe heartburn or ulcers (e.g. proton-pump inhibitors like omeprazole, pantoprazole, lansoprazole)
theophylline (used to treat asthma and other lung diseases)
amiodarone (to treat rhythm disorder)
nitrous oxide based anaesthesia (please talk to your doctor if you have planned an operation
vitamin preparations, which contain folic acid, folinic acid or any derivatives

You must not receive concurrent vaccination with live vaccines during treatment with methotrexate. If you are not sure talk to your doctor.

Some psoriasis patients have been reported to develop skin cancer with methotrexate and PUVA therapy (ultraviolet light therapy).

Radiation therapy during methotrexate therapy may increase the risk of necrosis (tissue damage resulting from the death of cells) in the soft tissue or bone tissue.

Ebetrex with food, drink and alcohol

During treatment with Ebetrex, you should not drink any alcohol this can increase toxicity (especially liver toxicity). You should avoid excessive consumption of coffee, soft drinks containing caffeine and black tea.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Pregnancy

Do not use Ebetrex during pregnancy or if you are trying to become pregnant. Methotrexate can cause birth defects, harm the unborn child or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very important that Methotrexate is not given to pregnant patients or patients planning to become pregnant. 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 by using reliable contraception throughout this time (see also section “Warnings and precautions”).

If you do become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. 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.

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

The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded. 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 should avoid fathering a child or to donate semen whilst taking methotrexate and for at least 3 months after treatment is stopped.

Driving and using machines

Side effects affecting the central nervous system, such as tiredness, drowsiness 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. This applies to an increased extent together with alcohol.

Ebetrex contains sodium

This medicinal product contains less than 1 mmol (23 mg) sodium per weekly dose, that is to say, essentially ‘sodium- free’.

3. HOW TO USE EBETREX

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

Important warning about the dose of Ebetrex (methotrexate):

Use Ebetrex only once a week for the treatment of rheumatoid arthritis, polyarthritic forms of juvenile idiopathic arthritis or psoriasis. Using too much of Ebetrex (methotrexate) may be fatal. Please read section 3 of this leaflet very carefully. If you have any questions, please talk to your doctor or pharmacist before you take this medicine.

Ebetrex should only be prescribed by physicians, who are familiar with the various characteristics of the medicinal products and its mode of action.

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.

In case of inadequate action and if tolerated well, Ebetrex the starting dose may be gradually increased by 2.5mg. Alternatively a higher starting dose can be used. The mean weekly dose is 15-20 mg. Generally, a weekly dose of 20 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.

Response to the therapy is expected after about 4-8 weeks. After discontinuing Ebetrex the symptoms may recur.

Use in children (children > 3 years) and adolescents

Dose in children (children > 3 years) 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/m²body surface area/week. However, regular check-ups should be done more often.

Adults with severe forms of psoriasis vulgaris or psoriatic arthritis

Recommended initial dose (relative to an average adult of 70kg body weight): A single test dose of 2.5 - 5 mg is recommended for the assessment of toxicity. With unchanged laboratory parameters 1 week later continuation with approx. 7.5 mg. The dose is gradually increased (in increments of 5 – 7.5 mg per week) while monitoring the laboratory parameters until an optimal treatment result is achieved. A weekly dose of 25 mg methotrexate should generally not be exceeded.

Once the desired outcome has been achieved, the dose should, as far as possible, be gradually reduced to the lowest maintenance dose still effective in the individual patient.

Response to therapy generally occurs after 4 – 8 weeks. Thereafter the therapy is continued or discontinued according to the clinical picture and laboratory parameter changes.

Elderly

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occurs with increased age.

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 4 – 8 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 including fatal course. 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

If you miss a dose, use within 24 hours of the specified day. If a longer delay should occur, talk to your doctor first. 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.

4. POSSIBLE SIDE EFFECTS

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

Side effects usually depend on dose level and treatment duration with Methotrexate.

Severe side effects may occur also at lower doses, which might lead to interruption or termination of therapy. Side effects might occur at any time during the therapy. Most side effects are reversible if recognised early. Termination of therapy does not always completely resolve all side effects.

However, some of the severe side effects named below may result in sudden death in very rare cases. Some side effects might occur after end of therapy.

Please talk to your doctor.

If you develop any of the following side effects, contact your doctor immediately as these might be signs of life-threatening side effects which need to be treated immediately. Your doctor might decide to decrease the dose or stop therapy.

Serious side effects

Allergic symptoms like rash or itching (especially affecting your whole body), swelling of the hands, feet, ankles, eyelids, face, lips, mouth or throat (which might lead to difficulties in swallowing or breathing), sudden wheeziness, difficulty in breathing, and feeling you are going to faint (these might be signs of severe allergic reactions or an anaphylactic shock) (may affect up to 1 in 100 patients)
Lung complaints (symptoms may be general illness; dry, irritating cough; shortness of breath, breathlessness at rest, chest pain, or fever) – these can be signs for pneumonia, interstitial pneumonitis or alveolitis (may affect up to 1 in 10 patients)
Spitting or coughing blood
Symptoms of liver failure like yellowing of the skin (jaundice) and whites of the eyes, dark urine, nausea, vomiting, loss of appetite, pain on the right side of the abdomen and itching (may affect up to 1 in 100 patients)
Symptoms of kidney failure like swelling of the hands, ankles or feet or changes in frequency of urination or decrease or absence of urine (may affect up to 1 in 100 patients)
Symptoms of an infection like fever, shivering, pain, sore throat. Methotrexate can decrease your resistance to infections; serious infections like a special form of pneumonia (pneumocystis jirovecii pneumonia) might occur (may affect up to 1 in 10,000 patients) or blood poisoning (may affect up to 1 in 1,000 patients)
Fever, sore throat, mouth ulcers, generally feeling unwell and tired, nose-bleed, tiny red spots on the skin may be symptoms of bone marrow damage (may affect up to 1 in 10 patients)
Ulcers in the mouth and throat (may affect more than 1 in 10 patients)
Pain in the stomach area, nausea, vomiting and fever as these can be signs of pancreatitis (may affect up to 1 in 100 patients)
Strong pain in the abdominal area, fever, nausea, vomiting, severe diarrhoea, black or tarry stools or change in bowel habits as these could be symptoms of complications in the gastrointestinal tract like ulcers (may affect up to 1 in 100 patients) or perforation of the bowel (frequency not known)
Severe toxic skin reactions including bladder formation and detachment of the top layer of the skin (Stevens-Johnson syndrome, toxic epidermal necrolysis/Lyell’s syndrome). The skin reactions are associated with severe disturbance of the general condition and fever. The skin reaction can be life threatening (may affect up to 1 in 100 patients)
Symptoms of thrombosis (blood clot) like pain or pressure in the chest, pain in the arms, back, neck or jaw, shortness of breath, numbness or weakness in one half of the body, speech disorders, headache or drowsiness (may affect up to 1 in 1,000 patients)
Cough, chest pain, sudden shortness of breath or coughing blood; these could be symptoms of a lung embolism (blood clot in the lung) (may affect up to 1 in 1,000 patients)

The following side effects have also been reported:

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

Reduced blood cell formation with decrease in white blood cells and/or platelets (leukopenia, thrombocytopenia)
Headache, dizziness
Cough
Loss of appetite, nausea (feeling sick), vomiting, diarrhoea, (particularly within 24 – 48 hours after first application of methotrexate), tummy pain
Inflammation and ulcers in the mouth and throat (particularly within 24 – 48 hours after first application of methotrexate)
Increase in liver enzymes in blood tests
Hair loss
Decreased creatinine clearance (can be determined with a blood test at the doctor and shows the worsening of kidney function)
Feeling weak

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

Shingles (herpes zoster)
Anaemia
Decrease in the number of red and white blood cells and platelets, sharp fall in certain white blood cells (agranulocytosis), blood cell formation disorders (pancytopenia)
tiredness, drowsiness
Tingling, tickling, pricking (paraesthesia)
Burning of the skin, rash, reddening of the skin, itching
Increased sensitivity to sunlight, skin ulcers
Red eyes (conjunctivitis)

Uncommon (may affect up to 1 in 100 people)

Opportunistic infections (due to immune system not working properly) which may be fatal in some cases
Cancer of the lymphatic tissue (lymphoma) please also refer to section 2
Immune system not working properly leading to higher likelihood of infections/inflammation
Diabetes
Depression
Weakness of the entire left or right side of the body (hemiparesis)
Dizziness, confusion
Fits
Damage of the brain (encephalopathy/leukoencephalopathy)
Inflammation of blood vessels (vasculitis)
Allergic vasculitis
Formation of scar tissue in the lung (pulmonary fibrosis), fluid around the lungs
Ulcers and bleeding in the digestive tract
Inflammation of the pancreas
Liver damage, liver fattening, formation of scar tissue in the liver (liver fibrosis), chronic liver damage (liver cirrhosis)
Drop of serum albumin
Nettle rash (alone), darkening of skin,
Increase of rheumatic nodules
Painful psoriasis
Herpes-like skin lesions
Joint or muscle pain
Osteoporosis (reduction of bone mass)
Inflammation and ulcers of the bladder (possibly with blood in the urine), problems to empty the bladder, reduced/no or painful urination
Malformations in the unborn child
Inflammation and ulcers of the vagina
Fever

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

Very large red blood cells (megaloblastic anaemia)
Mood fluctuations
Temporary problems with perception
Weakness of voluntary movement in the whole body
Problems with speaking (aphasia, dysarthria)
Severe visual disturbances (blurred or cloudy vision), blood clots in the retina
Low blood pressure
Blood clots (thromboembolic events)
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
Erythema multiforme, red skin rash
Bone fracture due to exertion
Electrolyte disturbances, increase in urea, creatinine and uric acid in the blood (azotaemia)
Abortion
Defective sperm formation (goes back to normal after end of treatment)
Menstruation disorders (goes back to normal after end of treatment)

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

Hepatitis caused by herpes viruses (herpes simplex hepatitis), infections caused by fungi (histoplasmosis, cryptococcosis), by bacteria (nocardiosis), by viruses (cytomegalovirus infections, including pneumonia)
Cold sores (herpes simplex)
Anaemia due to inadequate formation of red blood cells (aplastic anaemia), increase in eosinophilic granulocytes in the blood (eosinophilia), reduction of neutrophil granulocytes in the blood (neutropenia), swollen lymph nodes in the head and neck, under the armpits and in the groins (partly reversible), uncontrolled proliferation of lymphocytes (partly reversible)
Immune deficiency (hypogammaglobulinaemia)
Hepatitis
Pain and muscle weakness in the extremities
Changes in sense of taste (metallic taste)
Inflammation of the lining of the brain causing paralysis or vomiting
Swelling around the eyes, inflammation of the eyelid, tearing, increased light sensitivity, transient blindness, impaired vision
Inflammation of the sac around the heart (pericarditis), obstruction of cardiac filling by effusion in the pericardium (pericardial tamponade), fluid accumulation between the pericardial leaves (pericardial effusion)
Abnormal results in lung function test with difficulty in breathing and cough
Vomiting blood
Death of liver cells (liver necrosis), acute liver degeneration, liver failure
Deep infection of hair follicles (furunculosis), permanent enlargement of the capillaries visible on the skin (telangiectasia), acute inflammation of the nail bed
Blood and/or protein in the urine
Death of the unborn child
Problems in the formation of eggs (women) and sperm (men)
Menstrual cycle disturbances
Loss of sex drive
Problems having an erection
Enlargement of male breast
Vaginal discharge
Infertility
Sensation of numbness or tingling / having less sensitivity to stimulation than normal
Skin that is more sensitive to sunlight than normal. You may get a skin rash, redness, swelling or severe sunburn.

Not known (frequency cannot be estimated from the available data):

pneumonia
reactivation of hepatitis B infection, worsening of hepatitis C infection
bleeding from the lungs
skin cancer (please refer also to section 2)
increase in the pressure of cerebrospinal fluid with symptoms like headache, nausea, vomiting, increased blood pressure, confusion; damage of nervous system (neurotoxicity), inflammation of brain lining (arachnoiditis), paralysis of legs (paraplegia), stupor, problems with coordination of movements (ataxia), dementia,
non-inflammatory eye disorder (retinopathy)
hypoxia (lack of oxygen in the tissues)
non-infectious inflammation of the lining of the abdomen characterised by stomach pain and sensitivity to pressure (peritonitis)
toxic megacolon, (serious complication due to massive enlargement of the colon combined with severe pain), intestinal perforation
inflammation of tongue
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Dermatitis
Bone damage in general and in the jaw (secondary to excessive growth of white blood cells)
Urogenitory dysfunction
Chest pain, chills, damage of tissue at site of injection
redness and shedding of skin
swelling

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. Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions were observed, decreasing during therapy.

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store. By reporting side effects you can help provide more information on the safety of this medicine.

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 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. 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 medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Ebetrex contains

The active substance is methotrexate.

Each ml solution for injection contains 10 mg of methotrexate (as 10.97 mg of methotrexate disodium).

Each pre-filled syringe with 0.75 ml solution for injection contains 7.5 mg of methotrexate.

Each pre-filled syringe with 1 ml solution for injection contains 10 mg of methotrexate.

Each pre-filled syringe with 1.5 ml solution for injection contains 15 mg of methotrexate.

Each pre-filled syringe with 2 ml solution for injection contains 20 mg of methotrexate.

The other ingredients are sodium chloride, sodium hydroxide (for pH adjustment) and water for injections.

Ebetrex pre-filled syringes contain a clear, yellow solution for injection that is free of particles.

Ebetrex is available in pre-filled syringes of colourless glass (type I according to Ph.Eur.) with a capacity of 1.25 ml, 2.25 ml or 3.00 ml, an elastomeric tip cap and an elastomeric plunger stopper.

Pack sizes:

1 x 0.75 ml, 4 x 0.75 ml, 5 x 0.75 ml

1 x 1.0 ml, 4 x 1.0 ml, 5 x 1.0 ml

1 x 1.5 ml, 4 x 1.5 ml, 5 x 1.5 ml

1 x 2.0 ml, 4 x 2.0 ml, 5 x 2.0 ml

Single-use injection needles and alcohol pads.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Sandoz Limited

Park View, Riverside Way

Watchmoor Park

Camberley, Surrey

GU15 3YL

United Kingdom

Manufacturer

Ebewe Pharma Ges.m.b.H. Nfg.KG, A-4866 Unterach, Austria

This leaflet was last revised in 02/2024.

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The following information is intended for 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