Ebetrexat

Package leaflet: Information for the patient

Ebetrexat, 20 mg/ml, solution for injection in pre-filled syringe
Methotrexatum
Please read all of this leaflet carefully before using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm others, even if their symptoms are the same as yours.
• If you experience any adverse effects, including any not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of the leaflet:

1. What Ebetrexat is and what it is used for
2. Important information before using Ebetrexat
3. How to use Ebetrexat
4. Possible side effects
5. How to store Ebetrexat
6. Contents of the package and other information

1. What Ebetrexat is and what it is used for

Ebetrexat is a medicine with the following properties:

• affects the proliferation of certain rapidly dividing cells (has antineoplastic activity);
• suppresses undesirable immune responses (has immunosuppressive activity);
• has anti-inflammatory effects.

Ebetrexat is used in the treatment of patients with:

• active rheumatoid arthritis (RA) in adults;
• polyarticular forms (affecting 5 or more joints) of severe active juvenile idiopathic arthritis (JIA), when treatment with non-steroidal anti-inflammatory drugs (NSAIDs) has proven ineffective;
• severe, treatment-resistant, disabling psoriasis in patients who have not responded adequately to other treatments such as phototherapy, photochemotherapy (PUVA), and retinoids, as well as severe psoriatic arthritis (psoriatic arthropathy) in adult patients.

2. Important information before using Ebetrexat

If you have any questions, consult your doctor or pharmacist before using Ebetrexat.

When not to use Ebetrexat

• if you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6);
• if you have severe kidney disease (your doctor will assess whether the disease is severe);
• if you have severe liver disease (your doctor will assess whether the disease is severe);
• if you have blood disorders;
• if you consume large amounts of alcohol;
• if you have immune system disorders;
• if you have severe or concurrent infections, e.g. tuberculosis or HIV;
• if you have active peptic ulcer disease (including oral ulcers);
• if you are pregnant or breastfeeding (see section "Pregnancy, breastfeeding and fertility");
• if you are simultaneously receiving vaccines containing live microorganisms.

Warnings and precautions
Before starting treatment with Ebetrexat, discuss with your doctor if:

• you have diabetes and are treated with insulin;
• you have inactive, chronic infections (e.g. tuberculosis, hepatitis B or C, shingles);
• you have or have had kidney or liver disease in the past;
• you have lung function disorders;
• you have fluid accumulation in the abdominal cavity or in the space between the lungs and the chest wall (ascites, pleural effusion);
• you are dehydrated or have conditions leading to dehydration (vomiting, diarrhoea, oral mucositis).

Cases of acute pulmonary haemorrhage have been reported in patients with underlying rheumatologic disease during methotrexate treatment. If you experience haemoptysis (coughing up blood), seek immediate medical attention.

The medicine should be taken once weekly.
Incorrect use of methotrexate may lead to severe, potentially life-threatening adverse effects.
Please read section 3 of this leaflet carefully.
Methotrexate may increase skin sensitivity to sunlight. Avoid intense sun exposure and do not use solariums or tanning lamps without consulting your doctor.
To protect your skin from intense sunlight, wear appropriate clothing or use a high-protection sunscreen.
During methotrexate treatment, radiation-induced skin inflammation (radiation recall dermatitis) or sunburn may recur (so-called "recall reaction").
If you, your partner or caregiver notice new onset or worsening of neurological symptoms, including general muscle weakness, vision disturbances, changes in thinking, memory and orientation leading to disorientation and personality changes, contact your doctor immediately, as these may be signs of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).

Children and adolescents
Dosage depends on the patient's body weight. Use of Ebetrexat is not recommended in patients under 3 years of age due to insufficient experience in this age group.
Treatment with Ebetrexat in children should be closely monitored by an experienced specialist to detect any adverse reactions as early as possible.

Elderly patients
During methotrexate treatment, elderly patients should be carefully monitored to detect any adverse reactions as early as possible. Due to age-related impairment of liver and kidney function and reduced folate reserves in the body, methotrexate doses used in elderly patients should be relatively low.

Exposure to UV radiation during Ebetrexat therapy may exacerbate skin changes associated with psoriasis.

Recommended monitoring tests and precautions
Even after administration of low doses of Ebetrexat, severe adverse effects may occur. To detect these effects early, your doctor must perform regular check-ups and laboratory tests.

Before starting treatment
Prior to initiating therapy, blood tests will be performed to check whether blood cell counts are adequate. Blood will also be tested to evaluate liver function and to rule out hepatitis. Serum albumin levels (a blood protein), liver inflammation status (liver infection), and kidney function will also be assessed. Your doctor may also decide to perform additional liver tests, some of which may involve imaging studies of the organ, while others may require a small tissue sample for more detailed examination. Your doctor may also check for tuberculosis and order a chest X-ray or lung function tests.

During treatment:
Your doctor may perform the following tests:

• examination of the mouth and throat for mucosal changes such as inflammation or ulceration;
• blood tests / complete blood count with blood cell counts and measurement of methotrexate serum concentration;
• blood tests to monitor liver function;
• imaging tests to monitor liver status;
• liver biopsy (taking a small tissue sample for detailed examination);
• blood tests to monitor kidney function;
• monitoring of the respiratory system and, if necessary, lung function tests.

It is very important that you attend these scheduled check-ups.
If any of the test results are abnormal, your doctor will adjust your treatment accordingly.

Special precautions for the use of Ebetrexat
Methotrexate temporarily impairs sperm and egg cell production; in most cases, this effect is reversible. Methotrexate may cause miscarriage and severe congenital malformations. Women should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends. Men should avoid fathering a child during methotrexate treatment and for at least 3 months after treatment ends. See also section "Pregnancy, breastfeeding and fertility".

Ebetrexat and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking, have recently taken, or plan to take. If your doctor prescribes other medicines, inform them that you are using Ebetrexat.

It is especially important to inform your doctor about the use of:

• other medicines used for rheumatoid arthritis or psoriasis such as leflunomide, sulfasalazine (also used in the treatment of ulcerative colitis), acetylsalicylic acid, phenylbutazone or aminophenazone;
• alcohol (should be avoided);
• live vaccines;
• azathioprine (used to prevent organ transplant rejection);
• retinoids (used in the treatment of psoriasis and other skin diseases);
• anticonvulsants (to prevent epileptic seizures);
• anticancer drugs;
• barbiturates (injectable sleeping agents);
• sedatives;
• oral contraceptives;
• probenecid (used in the treatment of gout);
• antibiotics;
• penicillins – may reduce methotrexate excretion, potentially increasing adverse effects;
• metamizole (synonyms: novaminsulfone and dipyrone) (a strong analgesic and/or antipyretic);
• pyrimethamine (used for prevention and treatment of malaria);
• vitamin preparations containing folic acid;
• proton pump inhibitors (used to treat severe heartburn or ulcers);
• theophylline (used to treat asthma).

Ebetrexat with food, drink and alcohol
During treatment with Ebetrexat, avoid alcohol consumption as well as excessive intake of coffee, caffeine-containing beverages and black tea. During Ebetrexat treatment, drink plenty of fluids, as dehydration (reduced body water) may intensify the toxic effects of Ebetrexat.

Pregnancy, breastfeeding and fertility
If you are pregnant or breastfeeding, suspect you may be pregnant, or are planning to have a baby, consult your doctor or pharmacist before using this medicine.

Pregnancy
Do not use Ebetrexat if you are pregnant or trying to become pregnant. Methotrexate may cause congenital malformations, harm the unborn child, or cause miscarriage. This is associated with developmental abnormalities of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that women who are pregnant or planning pregnancy do not take methotrexate. If you are of childbearing age, pregnancy must be definitively ruled out before starting treatment, using appropriate measures such as a pregnancy test.

You should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends, using reliable contraceptive methods throughout this period (see also section "Warnings and precautions").

If you become pregnant during treatment or suspect you may be pregnant, contact your doctor immediately. You should seek advice regarding the potential harmful effects of treatment on the child.

If you plan to become pregnant, consult your doctor, who may refer you to a specialist for advice before planned initiation of treatment.

Breastfeeding
Do not breastfeed during treatment, as methotrexate passes into breast milk. If your doctor considers methotrexate treatment absolutely necessary at this time, breastfeeding must be discontinued.

Male fertility
Available evidence does not indicate an increased risk of developmental abnormalities or miscarriages following paternal methotrexate use at doses below 30 mg/week. However, risk cannot be completely ruled out. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm and cause congenital malformations. Therefore, you should avoid impregnating your partner and must not be a sperm donor during methotrexate treatment and for at least 3 months after its completion.

Driving and operating machinery
During treatment with Ebetrexat, adverse effects on the central nervous system such as fatigue and dizziness may occur. In some cases, these may impair your ability to drive or operate machinery. If you experience fatigue or dizziness, do not drive or operate machinery.

Ebetrexat contains sodium chloride and sodium hydroxide
This medicinal product contains less than 1 mmol (23 mg) of sodium per weekly dose, i.e. it is considered "sodium-free".

3. How to use Ebetrexat

Important warning regarding the dosing of Ebetrexat (methotrexate):
In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis,
and psoriasis, Ebetrexat must be used only once a week. Taking a higher amount
of Ebetrexat (methotrexate) may result in death. Please read section 3 of this leaflet carefully. If you have any questions, consult your doctor or pharmacist before taking the medicine.
Ebetrexat may only be prescribed by physicians familiar with the properties of this medicine and its mode of action.
This medicine should always be used exactly as prescribed by your doctor. If in doubt, consult your doctor or pharmacist.
Ebetrexat is administered only once a week. Together with your doctor, select an appropriate day of the week for the injection.
Incorrect use of Ebetrexat may lead to severe adverse reactions, which may be fatal.

Typical dosage:
Dosing in patients with rheumatoid arthritis
The recommended initial dose is 7.5 mg of methotrexate once weekly. Ebetrexat is administered as a single subcutaneous, intramuscular, or intravenous injection (see section "Method of administration and duration of treatment").
If Ebetrexat is not sufficiently effective and the patient tolerates it well, the doctor may increase the dose. The average weekly dose of methotrexate is 15–20 mg.
Weekly doses exceeding 25 mg should generally be avoided. After achieving the desired therapeutic effect, the dose should be gradually reduced, if possible, to the lowest effective maintenance dose.

Dosing in children and adolescents under 16 years of age with polyarticular forms of juvenile idiopathic arthritis
The recommended dose is 10–15 mg/m² body surface area (BSA) per week. If the response to treatment is inadequate, the doctor may increase the weekly dose to 20 mg/m² BSA. More frequent monitoring tests are then required. Due to limited data on intravenous administration in children and adolescents, methotrexate should be administered only via subcutaneous or intramuscular injection.
Use in children under 3 years of age is not recommended due to insufficient experience in this age group.

Adults with severe psoriasis or psoriatic arthritis
An initial test dose of 5–10 mg is recommended to assess potential toxic effects. This dose may be administered subcutaneously, intramuscularly, or intravenously.
If no changes in blood cell counts occur after one week, treatment may continue with a dose of approximately 7.5 mg. This dose may be gradually increased (by 5–7.5 mg per week, with monitoring of blood cell counts) until optimal treatment results are achieved. A weekly dose of 20 mg may be associated with significant toxicity. Doses exceeding 30 mg per week should not be used.
After achieving the desired therapeutic effect, the dose should be reduced weekly to the lowest effective maintenance dose for the individual patient.

Patients with impaired renal function
Dose reduction may be necessary in patients with impaired renal function.

Method of administration and duration of treatment
The duration of treatment is determined by the treating physician. Ebetrexat is administered by injection once a week! It is recommended to select one specific day each week for administering the injection.
Ebetrexat is administered via subcutaneous, intramuscular, or intravenous injection. Intravenous administration is not permitted in children and adolescents.
Long-term treatment with Ebetrexat is required for rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, and psoriatic arthritis.

Rheumatoid arthritis
Symptom improvement is usually observed after 4–8 weeks of treatment. After discontinuation of Ebetrexat, symptoms may recur.

Severe forms of psoriasis vulgaris and psoriatic arthritis (psoriasis arthropatica)
The expected response to treatment usually occurs after 2–6 weeks.
Treatment should be continued or discontinued depending on the severity of symptoms and laboratory test results.

At the beginning of treatment, Ebetrexat may be administered by medical personnel. However, the doctor may decide that the patient is capable of self-administering the injections. The patient will be properly trained in this regard. Never attempt self-injection without prior training.

Taking more Ebetrexat than prescribed
Always use the dose prescribed by your treating physician. Never change it independently.
If you suspect that a patient (or someone else) has taken more medicine than prescribed, contact your doctor or the emergency department of the nearest hospital immediately. Only a doctor can decide on the appropriate treatment depending on the severity of poisoning symptoms.
Methotrexate overdose may cause severe toxic reactions. Symptoms of overdose include: easy bruising or bleeding, unexplained fatigue, mouth ulcers, nausea, vomiting, black or bloody stools, coughing up blood or coffee-ground-like vomit, and reduced urine output. See also section 4.
Patients visiting a hospital or doctor should bring the medicine packaging with them.
The antidote used in case of poisoning is calcium folinate.

Missed dose of Ebetrexat
Do not take a double dose to make up for a missed dose. Continue taking the prescribed dose. Consult your doctor for advice.

Stopping Ebetrexat treatment
Do not interrupt or discontinue treatment with Ebetrexat without consulting your doctor.
If you suspect severe adverse reactions, seek medical advice immediately.
If you have any further questions or doubts about using this medicine, consult your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.
Immediately inform the doctor if the patient suddenly develops wheezing, difficulty breathing, swelling of the eyelids, face or lips, rash or itching (especially if affecting the whole body), or fainting (these may be symptoms of severe allergic reactions or anaphylactic shock).

Serious adverse effects
Contact a doctor immediately if any of the following adverse effects occur:

• Pulmonary symptoms (which may include general malaise; dry, irritating cough; shortness of breath, dyspnea at rest, chest pain or fever);
• Haemoptysis (coughing up blood);
• Severe skin peeling or formation of blisters on the skin (including inside the mouth, eyes and genital organs);
• Unexplained bleeding (including vomiting blood) or development of bruises;
• Severe diarrhoea;
• Oral mucosal ulcers;
• Black or tarry stools;
• Blood in urine or faeces;
• Tiny red spots on the skin;
• Fever;
• Yellowing of the skin (jaundice);
• Pain or difficulty passing urine;
• Feeling thirsty and (or) frequent urination;
• Seizures;
• Loss of consciousness;
• Blurred vision or visual disturbances.

The following adverse effects have also been reported:
Very common (may affect more than 1 in 10 people):

• Loss of appetite, nausea, vomiting, abdominal pain
• Inflammation and ulceration of the mouth and throat
• Increased liver enzyme activity.

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

• Decreased production of blood cells with reduced numbers of white and (or) red blood cells or platelets (leukopenia, anaemia, thrombocytopenia)
• Headache
• Feeling tired, drowsiness
• Tingling, pricking or burning sensation of the skin, rash, skin redness, itching
• Lung inflammation
• Diarrhoea.

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

• Herpes zoster
• Lymphoma (which in many cases regresses after discontinuation of the medicine)
• Decreased number of blood cells and platelets
• Severe allergic reactions
• Diabetes
• Depression
• Weakness of muscles on the left or right side of the body
• Dizziness, disorientation
• Seizures
• Brain damage (leukoencephalopathy/encephalopathy)
• Vasculitis
• Lung damage, presence of fluid around the lungs
• Gastrointestinal ulcers and haemorrhage
• Pancreatitis
• Liver function disorders
• Decreased blood protein levels
• Urticaria (without other symptoms), skin photosensitivity, brown skin discoloration
• Severe skin toxic reactions, including blistering and skin peeling (Stevens-Johnson syndrome, Lyell's syndrome)
• Alopecia
• Enlargement of rheumatoid nodules
• Pain in psoriatic lesions
• Sunburn-like reactions due to increased skin sensitivity to sunlight
• Joint or muscle pain
• Osteoporosis (reduced bone mass)
• Inflammation and ulceration of the urinary bladder (may present with haematuria), painful urination
• Congenital malformations in the fetus
• Inflammation and ulceration of the vagina
• Burning sensation or tissue damage after intramuscular injection of the medicine.

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

• Sepsis
• Presence in blood of very large red blood cells (megaloblastic anaemia)
• Mood swings
• Transient perception disturbances
• Weakness of voluntary movements of all muscles
• Difficulty speaking
• Severe eye disorders
• Low blood pressure
• Blood clots
• Sore throat
• Respiratory arrest
• Inflammation of the digestive tract, bloody stools
• Gingivitis
• Acute hepatitis
• Nail discoloration, nail loss
• Acne, presence of red or purple spots due to haemorrhages
• Stress fractures
• Electrolyte disturbances
• Miscarriage
• Abnormal sperm production
• Menstrual disorders.

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

• Cold sores (herpes labialis)
• Hepatitis
• Severe bone marrow failure
• Immune deficiency (hypogammaglobulinaemia)
• Pain
• Muscle weakness
• Taste disturbances (metallic taste in mouth)
• Meningitis (inflammation of the membranes covering the brain), causing paralysis or vomiting
• Eye redness
• Inflammation of the sac surrounding the heart (pericarditis), pericardial effusion
• Lung inflammation, breathing difficulties, bronchial asthma
• Vomiting blood
• Liver failure
• Infection of the nail fold of the hands, boils, presence of small visible blood vessels on the skin
• Protein in urine
• Fetal death
• Disorders in maturation of oocytes in women and sperm production in men
• Lack of libido
• Erectile dysfunction
• Vaginal discharge
• Infertility
• Mild skin reactions after subcutaneous administration of the medicine
• Lymphoproliferative disorders (overproduction of white blood cells)
• Numbness or tingling sensation, or reduced response to stimuli.

Frequency not known (cannot be estimated from available data):

• Infections, which in some cases may lead to death
• Swelling of lymph nodes
• Immune system function disorders
• Fever
• Inflammation of small blood vessels due to allergic reaction
• Peritonitis (inflammation of the membrane lining the abdominal cavity)
• Slow wound healing
• Bleeding from the lungs
• Jaw bone damage (due to overproduction of white blood cells)
• Tissue damage at injection site
• Skin redness and peeling
• Oedema.

After intramuscular administration, adverse effects (burning sensation) or tissue damage (formation of sterile abscess, fatty tissue atrophy) at the injection site may frequently occur.
Subcutaneous administration of methotrexate is well tolerated. Only mild skin reactions have been observed, which decrease during the course of treatment.
Methotrexate may cause a reduced number of white blood cells and weakened immunity to infections. If the patient develops an infection with symptoms such as fever and significant deterioration in general health, or fever with signs of local infection (sore throat and (or) laryngeal pain and (or) pain inside the mouth), or urinary disturbances, seek medical advice immediately. The doctor may recommend blood tests to determine whether the number of white blood cells has decreased (agranulocytosis). It is important to inform the doctor about the use of Ebetrexat.

Methotrexate may cause severe (sometimes life-threatening) adverse effects. Therefore, the doctor will recommend regular tests to detect possible changes in blood parameters (e.g. reduced number of white blood cells, low platelet count, presence of lymphoma) and in kidney and liver function.

Reporting of adverse effects
If any adverse effects occur, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. Adverse effects can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl
Adverse effects can also be reported to the marketing authorization holder.
Reporting adverse effects helps provide more information on the safety of the medicine.

5. How to store Ebetrexat

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pre-filled syringe and outer carton after EXP. The expiry date refers to the last day of the stated month.
Store the pre-filled syringe in the outer packaging to protect it from light.
Do not store above 25°C.
The medicine should be used immediately after opening.
Do not use Ebetrexat if the solution is not clear or contains particulate matter.
This medicine is for single use only. Any remaining solution must be discarded!
Neither the medicine nor its packaging should be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines or packaging no longer in use. This will help protect the environment.

6. Contents of the pack and other information

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

What Ebetrexat looks like and contents of the pack
Ebetrexat is available as a clear, yellowish injection solution in pre-filled syringes.
Each cardboard box 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 of injection solution, a single-use needle with or without protective housing, and alcohol swabs.
Collective packs contain 4, 5, 6, 12 or 30 pre-filled syringes (each pre-filled syringe in a cardboard box).

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Ebewe Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
4866 Unterach, Austria

Manufacturers
Ebewe Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
4866 Unterach, Austria
Salutas Pharma GmbH
Otto-von-Guericke-Allee 1
D-39179 Barleben, Germany
Fareva Unterach GmbH
Mondseestraße 11
4866 Unterach, Austria

For further information about the medicinal product and its trade names in other European Economic Area countries, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warszawa
tel. 22 209 70 00

Information intended exclusively for medical professionals

Ebetrexat, 20 mg/ml, solution for injection in pre-filled syringe
Instructions for use, handling, and disposal
The solution should be clear and free from particles.
Handling and disposal must comply with national regulations regarding
the preparation of other cytotoxic medicinal products. Healthcare personnel who are pregnant should
not have contact with and (or) administer the Ebetrexat product.
The medicinal product is for single use only. Any unused portion of the solution
must be discarded.
Any unused product or waste material must be disposed of in accordance with
local regulations for cytotoxic medicinal products.
Incompatibilities
Compatibility with other medicinal products has not been studied; therefore, this medicinal product must not be mixed with other medicinal products.
Special precautions for storage
Store in the outer packaging to protect from light.
Do not store above 25°C.

Step-by-step instructions for subcutaneous administration
Step 1

• Remove the inner packaging containing the pre-filled syringe and needle from the carton.
• Open the inner packaging by pulling the side flap and remove the pre-filled syringe.
• Unscrew the grey rubber stopper (covered with plastic) from the syringe, taking care not to touch the exposed tip of the pre-filled syringe (see Figure 1).

Figure 1.
Step 2

• Place the pre-filled syringe back into the inner packaging. The yellow solution will not leak from the syringe.
• Check the label on the plastic housing containing the needle. The label must not be damaged (see Figure 2).

Figure 2.
Step 3

• Remove the cap from the plastic needle housing by unscrewing and then pulling it off. See Figure 3.1.
• Carefully screw the needle, together with its plastic housing, onto the syringe until fully seated. See Figure 3.2.

Figure 3.1 Figure 3.2
Step 4

• Select an injection site on the abdomen or thigh and clean it with an alcohol swab. Do not touch the disinfected injection site (see Figures 4.1 and 4.2).

Figure 4.1 Figure 4.2
Step 5

• Remove the protective needle cap and set it aside.

• Do not touch the sterile needle. If contact occurs, consult a physician or pharmacist for a new needle. Hold the skin with two fingers to create a skin fold and insert the needle of the pre-filled syringe at an almost vertical position.

Step 6

• Insert the needle fully into the skin fold. Then slowly press the plunger of the syringe to inject the entire solution subcutaneously.

Step 7

• Carefully withdraw the needle from the skin fold and apply a gauze pad to the injection site. Do not rub the injection site, as this may cause irritation.

• To avoid accidental needlestick injury, dispose of the used syringe in a designated sharps container.

Package leaflet: information for the patient

Ebetrexat, 20 mg/ml, solution for injection in pre-filled syringe
Methotrexatum
Please read this leaflet carefully before using this medicine, as it contains
important information for the patient.

• Keep this leaflet for future reference.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not share it with others. This medicine may harm others, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Leaflet contents:

1. What Ebetrexat is and what it is used for
2. What you need to know before using 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

Ebetrexat is a medicine with the following properties:

• affects the proliferation of certain rapidly dividing cells (has antineoplastic activity);
• suppresses unwanted immune responses (has immunosuppressive activity);
• has anti-inflammatory effects.

Ebetrexat is used to treat patients with:

• active rheumatoid arthritis (RA) in adults;
• polyarticular-course (affecting 5 or more joints) severe active juvenile idiopathic arthritis (JIA), when treatment with non-steroidal anti-inflammatory drugs (NSAIDs) has been ineffective;
• severe, treatment-resistant psoriasis leading to disability in patients who have not responded adequately to other treatments such as phototherapy, photochemotherapy (PUVA), and retinoids, as well as in adult patients with severe psoriatic arthritis (psoriatic arthropathy).

2. Important information before using Ebetrexat

If you have any questions, consult your doctor or pharmacist before using Ebetrexat.

When not to use Ebetrexat

• if you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6);
• if you have severe kidney disease (your doctor will assess whether the disease is severe);
• if you have severe liver disease (your doctor will assess whether the disease is severe);
• if you have blood disorders;
• if you consume large amounts of alcohol;
• if you have immune system disorders;
• if you have severe or concurrent infections, e.g. tuberculosis or HIV;
• if you have active peptic ulcer disease (including oral ulceration);
• if you are pregnant or breastfeeding (see section "Pregnancy, breastfeeding and fertility");
• if you are simultaneously receiving vaccines containing live microorganisms.

Warnings and precautions
Before starting treatment with Ebetrexat, discuss with your doctor if:

• you have diabetes and are being treated with insulin;
• you have inactive, chronic infections (e.g. tuberculosis, hepatitis B or C, shingles);
• you have or have previously had kidney or liver disease;
• you have lung function disorders;
• you have fluid accumulation in the abdominal cavity or in the space between the lungs and chest wall (ascites, pleural effusion);
• you are dehydrated or have conditions leading to dehydration (vomiting, diarrhoea, oral mucositis).

Cases of acute pulmonary haemorrhage have been reported in patients with underlying rheumatological disease during methotrexate treatment. If you experience haemoptysis (coughing up blood), seek immediate medical advice.

The medicine should be taken once a week.
Incorrect use of methotrexate may lead to severe, potentially fatal adverse reactions.
Please read section 3 of this leaflet very carefully.

Methotrexate may increase skin sensitivity to sunlight. Avoid intense sun exposure and do not use sunbeds or tanning lamps without consulting your doctor. To protect your skin from strong sunlight, wear appropriate clothing or use a high-protection sunscreen.

During methotrexate treatment, recurrence of radiation-induced skin inflammation (radiation recall dermatitis) or sunburn (so-called "recall reaction") may occur.

If you, your partner or caregiver notice new onset or worsening of neurological symptoms, including general muscle weakness, visual disturbances, changes in thinking, memory and orientation leading to disorientation and personality changes, contact your doctor immediately, as these may be symptoms of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).

Children and adolescents
Dosage depends on the patient's body weight. Use of Ebetrexat is not recommended in patients under 3 years of age due to insufficient experience in this age group.
Treatment with Ebetrexat in children should be closely monitored by an experienced specialist to detect any adverse reactions as early as possible.

Elderly patients
During methotrexate treatment, elderly patients should be carefully monitored to detect any adverse reactions as early as possible. Due to age-related impairment of liver and kidney function and reduced folate reserves in the body, methotrexate doses used in elderly patients should be relatively low.

Exposure to UV radiation during Ebetrexat therapy may exacerbate skin lesions associated with psoriasis.

Recommended monitoring tests and precautions
Even after administration of low doses of Ebetrexat, severe adverse reactions may occur. To detect these reactions early, your doctor must perform regular monitoring and laboratory tests.

Before starting treatment
Blood tests will be performed before starting treatment to check whether blood cell counts are adequate. Blood will also be tested to assess liver function and to rule out hepatitis. Serum albumin (a blood protein), liver inflammation status (liver infection), and kidney function will also be evaluated. Your doctor may also decide to perform additional liver tests, some of which may involve imaging studies and others may require a small tissue sample for more detailed examination. Your doctor may also check for tuberculosis and may order a chest X-ray or lung function tests.

During treatment:
Your doctor may perform the following tests:

• examination of the mouth and throat for mucosal changes such as inflammation or ulceration
• blood tests including full blood count with blood cell counts and measurement of methotrexate serum concentration
• blood tests to monitor liver function
• imaging tests to monitor liver status
• liver biopsy (taking a small tissue sample for detailed examination)
• blood tests to monitor kidney function
• monitoring of the respiratory system and, if necessary, lung function tests.

It is very important that you attend these scheduled appointments.
If any of these test results are abnormal, your doctor will adjust your treatment accordingly.

Special precautions for the use of Ebetrexat
Methotrexate temporarily impairs the production of sperm and oocytes; in most cases, this effect is reversible. Methotrexate may cause miscarriage and severe congenital malformations. Women should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends. Men should avoid fathering a child during methotrexate treatment and for at least 3 months after treatment ends. See also section "Pregnancy, breastfeeding and fertility".

Ebetrexat and other medicines
Inform your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take. If your doctor prescribes other medicines, inform them that you are taking Ebetrexat.

It is especially important to inform your doctor if you are taking:

• other medicines used for rheumatoid arthritis or psoriasis such as leflunomide, sulfasalazine (also used in the treatment of ulcerative colitis), acetylsalicylic acid, phenylbutazone or aminophenazone;
• alcohol (should be avoided);
• live vaccines;
• azathioprine (used to prevent organ transplant rejection);
• retinoids (used in the treatment of psoriasis and other skin diseases);
• antiepileptic drugs (to prevent epileptic seizures);
• anticancer drugs;
• barbiturates (injectable sleeping medications);
• sedatives;
• oral contraceptives;
• probenecid (used in the treatment of gout);
• antibiotics;
• penicillins – may reduce methotrexate excretion, potentially increasing adverse effects;
• metamizole (synonyms: novaminsulfone and dipyrone) (a strong analgesic and/or antipyretic);
• pyrimethamine (used for prevention and treatment of malaria);
• vitamin preparations containing folic acid;
• proton pump inhibitors (used to treat severe heartburn or ulcers);
• theophylline (used in the treatment of asthma).

Ebetrexat with food, drink and alcohol
During treatment with Ebetrexat, avoid alcohol consumption as well as excessive intake of coffee, caffeine-containing beverages and black tea. During Ebetrexat treatment, drink plenty of fluids, as dehydration (reduced body water) may worsen the toxic effects of Ebetrexat.

Pregnancy, breastfeeding and fertility
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, consult your doctor or pharmacist before using this medicine.

Pregnancy
Do not use Ebetrexat if you are pregnant or trying to become pregnant. Methotrexate may cause congenital malformations, harm the unborn child or cause miscarriage. This is associated with developmental defects of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very important that women who are pregnant or planning pregnancy do not take methotrexate. If you are of childbearing age, pregnancy must be definitively ruled out before starting treatment, using appropriate measures such as a pregnancy test.

You should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends, using reliable contraception methods throughout this period (see also section "Warnings and precautions").

If you become pregnant during treatment or suspect you may be pregnant, contact your doctor immediately. You should seek advice regarding the potential harmful effects of treatment on the unborn child.

If you plan to become pregnant, consult your treating doctor, who may refer you to a specialist for advice before planned initiation of treatment.

Breastfeeding
Do not breastfeed during treatment, as methotrexate passes into breast milk. If your doctor considers methotrexate treatment absolutely necessary during this time, breastfeeding must be discontinued.

Male fertility
Available evidence does not indicate an increased risk of developmental defects or miscarriages following paternal methotrexate use at doses below 30 mg/week. However, risk cannot be completely excluded. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm and cause congenital malformations. Therefore, you should avoid impregnating your partner and must not be a sperm donor during methotrexate treatment and for at least 3 months after treatment ends.

Driving and using machines
During treatment with Ebetrexat, adverse reactions affecting the central nervous system such as fatigue and dizziness may occur. In some cases, these may impair your ability to drive or operate machinery. If you experience fatigue or dizziness, do not drive or operate machinery.

Ebetrexat contains sodium chloride and sodium hydroxide
This medicinal product contains less than 1 mmol (23 mg) of sodium per weekly dose, i.e. it is considered "sodium-free".

3. How to use Ebetrexat

Important warning regarding the dosing of Ebetrexat (methotrexate):
In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and psoriasis, Ebetrexat must be used only once a week. Taking more than the recommended amount of Ebetrexat (methotrexate) may result in death. Please read section 3 of this leaflet carefully. If you have any questions, consult your doctor or pharmacist before taking the medicine.
Ebetrexat may only be prescribed by physicians familiar with the properties and mode of action of this medicine.
This medicine should always be used exactly as directed by your doctor. If in doubt, consult your doctor or pharmacist.
Ebetrexat is administered only once a week. Together with your doctor, select a suitable day of the week on which the injection will be given.
Incorrect use of Ebetrexat may lead to severe adverse reactions, which may result in death.

Typical dosage:
Dosing in patients with rheumatoid arthritis
The recommended initial dose is 7.5 mg of methotrexate once weekly. Ebetrexat is administered as a single subcutaneous, intramuscular, or intravenous injection (see section "Method of administration and duration of treatment").
If Ebetrexat is not sufficiently effective and the patient tolerates it well, the doctor may increase the dose. The average weekly dose of methotrexate is 15–20 mg.
Weekly doses exceeding 25 mg should generally not be used. After achieving the desired therapeutic effect, the dose should be gradually reduced, if possible, to the lowest effective maintenance dose.

Dosing in 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 (BSA) per week. If the response to treatment is inadequate, the doctor may increase the weekly dose to 20 mg/m^2 BSA. More frequent monitoring tests are required in such cases. Due to limited data on intravenous administration in children and adolescents, methotrexate should be administered only via subcutaneous or intramuscular injection.
The use of this medicine is not recommended in children under 3 years of age due to insufficient experience in this age group.

Adults with severe psoriasis or psoriatic arthritis
An initial test dose of 5–10 mg is recommended to assess potential toxic effects. This dose may be administered subcutaneously, intramuscularly, or intravenously.
If no changes in blood cell counts occur after one week, treatment may continue with a dose of approximately 7.5 mg. This dose may be gradually increased (by 5–7.5 mg per week, with monitoring of blood cell counts) until optimal treatment results are achieved. A weekly dose of 20 mg may be associated with significant toxicity. The weekly dose should not exceed 30 mg.
After achieving the desired therapeutic effect, the dose should be reduced weekly until the lowest effective maintenance dose for the individual patient is reached.

Patients with impaired renal function
In patients with impaired renal function, dose reduction may be necessary.

Method of administration and duration of treatment
The duration of treatment is determined by the treating physician. Ebetrexat is administered as an injection once a week! It is recommended to select one specific day each week for administering the injection.
Ebetrexat is administered via subcutaneous, intramuscular, or intravenous injection. Intravenous administration is not permitted in children and adolescents.
Long-term treatment with Ebetrexat is required for rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, and psoriatic arthritis.

Rheumatoid arthritis
Symptom relief is usually observed after 4–8 weeks of treatment. After discontinuation of Ebetrexat, symptoms may recur.

Severe forms of psoriasis vulgaris and psoriatic arthritis (psoriasis arthropatica)
The expected response to treatment usually occurs after 2–6 weeks.
Treatment should be continued or discontinued depending on the severity of symptoms and laboratory test results.

At the beginning of treatment, Ebetrexat may be administered by medical personnel. However, the doctor may decide that the patient is capable of self-injecting Ebetrexat independently. The patient will be properly trained for this. Never attempt self-injection without prior training.
Further information is provided in section "Instructions for using Ebetrexat in pre-filled syringe".

Taking more than the recommended dose of Ebetrexat
Always use the dose prescribed by your treating physician. Never change the dose independently.
If you suspect that a patient (or someone else) has taken more than the recommended dose, contact your doctor or the nearest hospital emergency department immediately. Only a doctor can decide on the appropriate treatment depending on the severity of poisoning symptoms.
Methotrexate overdose may cause severe toxic reactions. Symptoms of overdose include: easy bruising or bleeding, unexplained weakness, mouth ulcers, nausea, vomiting, black or bloody stools, coughing up blood or vomiting material resembling coffee grounds, and reduced urine output. See also section 4.
Patients visiting a hospital or doctor should bring the medicine packaging with them.
The antidote used in case of poisoning is calcium folinate.

Missed dose of Ebetrexat
Do not take a double dose to make up for a missed dose. Continue taking the prescribed dose as directed. Consult your doctor for advice.

Stopping Ebetrexat treatment
Do not interrupt or discontinue treatment with Ebetrexat without consulting your doctor.
If you suspect severe adverse reactions, seek medical advice immediately.
If you have any further questions or uncertainties regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
You should immediately inform the doctor if the patient suddenly develops wheezing,
difficulty breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting
the whole body), or fainting (these may be symptoms of severe allergic reactions or
anaphylactic shock).

Severe adverse reactions
You should contact the doctor immediately if any of the following adverse reactions occur:

• Lung problems (symptoms may include general malaise; dry, irritating cough; shortness of breath, breathlessness at rest, chest pain or fever);
• Haemoptysis, i.e. coughing up blood-stained sputum;
• Severe peeling of the skin or formation of blisters on the skin (including inside the mouth, eyes and genital organs);
• Unexplained bleeding (including vomiting blood) or development of bruises;
• Severe diarrhoea;
• Ulceration of the mucous membrane of the mouth;
• Black or tarry stools;
• Blood in the urine or faeces;
• Small red spots on the skin;
• Fever;
• Yellowing of the skin (jaundice);
• Pain or difficulty passing urine;
• Feeling thirsty and/or frequent urination;
• Seizures (fits);
• Loss of consciousness;
• Blurred vision or visual disturbances.

The following adverse reactions have also been reported:
Very common (may affect more than 1 in 10 people):

• Loss of appetite, nausea, vomiting, abdominal pain
• Inflammation and ulceration of the mouth and throat
• Increased liver enzyme activity.

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

• Decreased production of blood cells with reduced numbers of white and/or red blood cells or platelets (leukopenia, anaemia, thrombocytopenia)
• Headache
• Feeling tired, drowsiness
• Tingling, pricking or burning sensation of the skin, rash, redness of the skin, itching
• Lung inflammation
• Diarrhoea.

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

• Shingles (herpes zoster)
• Lymphoma (which often resolves after discontinuation of the medicine)
• Decreased number of blood cells and platelets
• Severe allergic reactions
• Diabetes
• Weakness of the left or right side of the body
• Dizziness, disorientation
• Seizures
• Brain damage (leukoencephalopathy/encephalopathy)
• Vasculitis (inflammation of blood vessels)
• Lung damage, fluid accumulation around the lungs
• Ulceration and bleeding from the gastrointestinal tract
• Pancreatitis
• Liver function disorders
• Decreased blood protein levels
• Urticaria (without other symptoms), increased sensitivity of the skin to sunlight, brownish skin discoloration
• Severe skin toxic reactions, including blistering and skin peeling (Stevens-Johnson syndrome, Lyell's syndrome)
• Hair loss
• Enlargement of rheumatoid nodules
• Pain in psoriatic lesions
• Sunburn-like reactions due to increased skin sensitivity to sunlight
• Joint or muscle pain
• Osteoporosis (reduced bone mass)
• Inflammation and ulceration of the urinary bladder (may present with haematuria), painful urination
• Congenital malformations in the fetus
• Inflammation and ulceration of the vagina
• Burning sensation or tissue damage after intramuscular injection of the medicine.

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

• Sepsis
• Presence in the blood of very large red blood cells (megaloblastic anaemia)
• Mood swings
• Transient disturbances in perception
• Impaired voluntary muscle movements
• Difficulty speaking
• Severe eye disorders
• Low blood pressure
• Blood clots
• Sore throat
• Respiratory arrest
• Gastrointestinal inflammation, bloody stools
• Gingivitis
• Acute hepatitis
• Nail discoloration, nail loss
• Acne, presence of red or purple spots due to haemorrhages
• Stress fractures
• Electrolyte disturbances
• Miscarriage
• Abnormal sperm production
• Menstrual disorders.

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

• Cold sores (herpes labialis)
• Hepatitis
• Severe bone marrow failure
• Immune deficiency (hypogammaglobulinaemia)
• Pain
• Muscle weakness
• Taste disturbances (metallic taste in the mouth)
• Meningitis (inflammation of the membranes covering the brain), causing paralysis or vomiting
• Redness of the eyes
• Pericarditis (inflammation of the sac surrounding the heart), fluid in the pericardium
• Lung inflammation, breathing difficulties, bronchial asthma
• Vomiting blood
• Liver failure
• Infection of the nail fold of the hands, abscesses, presence of small visible blood vessels on the skin
• Presence of protein in the urine
• Fetal death
• Impaired maturation of egg cells in women and impaired sperm production in men
• Loss of libido
• Erectile dysfunction
• Hot flushes
• Infertility
• Mild skin reactions after subcutaneous administration of the medicine
• Lymphoproliferative disorders (overproduction of white blood cells)
• Numbness or tingling sensation, or reduced response to stimuli.

Frequency not known (cannot be estimated from available data):

• Infections, which in some cases may lead to death
• Swelling of lymph nodes
• Immune system function disorders
• Fever
• Inflammation of small blood vessels due to allergic reaction
• Peritonitis (inflammation of the membrane lining the abdominal cavity)
• Slow wound healing
• Bleeding from the lungs
• Jaw bone damage (due to overproduction of white blood cells)
• Tissue necrosis at the injection site
• Redness and peeling of the skin
• Oedema.

After intramuscular administration, adverse reactions (burning sensation) or
tissue damage (formation of sterile abscess, fatty tissue atrophy) at the injection site may frequently occur.
Subcutaneous administration of methotrexate is well tolerated. Only mild skin reactions have been observed,
which decrease during the course of treatment.
Methotrexate may cause a reduced number of white blood cells and weakened immunity to
infections. If the patient develops an infection with symptoms such as fever and significant worsening
of general health, or fever and signs of local infection (sore throat and/or laryngeal pain and/or pain in the mouth), or urinary disturbances, medical advice should be sought immediately.
The doctor may recommend blood tests to determine whether the number of white blood cells has decreased (agranulocytosis).
It is important to inform the doctor about the use of Ebetrexat.
Methotrexate may cause severe (sometimes life-threatening) adverse reactions. Therefore,
the doctor will recommend regular tests to detect possible changes in blood parameters
(e.g. reduced number of white blood cells, low platelet count, presence of lymphoma) and changes
in the kidneys and liver.

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed
in this leaflet, you should inform your doctor, pharmacist or nurse. Adverse reactions
can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw
tel.: + 48 22 49 21 301, fax: + 48 22 49 21 309, website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Ebetrexat

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the pre-filled syringe and outer carton after EXP. The expiry date refers to the last day of the specified month.
Store the pre-filled syringe in the outer packaging to protect it from light.
Do not store above 25°C.
The medicine should be used immediately after opening.
Do not use Ebetrexat if the solution is not clear or contains particles.
This medicine is for single use only. Any unused solution must be discarded!
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

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

What Ebetrexat looks like and contents of the pack
Ebetrexat is available as a clear, yellowish injection solution in pre-filled syringes.
Each cardboard box 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 of injection solution, single-use needle with or without protective housing, and alcohol swabs.
Multipack containers contain 4, 5, 6, 12 or 30 pre-filled syringes (each pre-filled syringe in a cardboard box).

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Ebewe Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
4866 Unterach, Austria

Manufacturer
Ebewe Pharma Ges.m.b.H. Nfg. KG
Mondseestrasse 11
4866 Unterach, Austria
Salutas Pharma GmbH
Otto-von-Guericke-Allee 1
D-39179 Barleben, Germany
Fareva Unterach GmbH
Mondseestraße 11
4866 Unterach, Austria

For further information about the medicinal product and its names in other European Economic Area countries, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warsaw
tel. 22 209 70 00

Instructions for use of Ebetrexat pre-filled syringe
The yellow-coloured solution should be clear and free from particles. It must not be mixed with other medicinal products.
Handling and disposal must comply with national regulations concerning the preparation of other medicines which may damage cells. Pregnant women, including pregnant healthcare workers, should not handle or (and/or) administer Ebetrexat.
To correctly use the pre-filled syringe, strictly follow the steps of the subcutaneous injection instructions below:

Step 1

• Remove the inner packaging containing the pre-filled syringe and needle from the box.
• Open the inner packaging by pulling the side flap. Remove the pre-filled syringe.
• Unscrew the grey rubber stopper (covered with plastic) from the syringe, without touching the exposed tip of the pre-filled syringe (see Figure 1).

Figure 1.

Step 2

• Place the syringe back into the inner packaging. The yellow solution will not leak from the syringe.
• Check the label on the plastic housing containing the needle. The label must not be damaged! (see Figure 2)

Figure 2.

Step 3

• Remove the cap from the plastic needle housing by unscrewing and then pulling it off. See Figure 3.1.
• Carefully screw the needle, together with its plastic housing, firmly onto the syringe until it stops. See Figure 3.2.

Figure 3.1 Figure 3.2

Step 4

• Select an injection site on the abdomen or thigh and clean it with an alcohol swab. Do not touch the disinfected injection site (see Figures 4.1 and 4.2).

Figure 4.1 Figure 4.2

Step 5

• Pull the housing straight backward to remove it from the needle. Check that the indicator is blue (see arrow in Figure 5.1).
• The syringe is now ready for use. Caution: The needle cap must not be reattached to the needle to avoid accidental activation of the safety mechanism. Do not touch the needle shield before injecting the medicine (see Figure 5.2). Any pressure on the shield may cause the safety mechanism to close, rendering the needle unusable. In such a case, the blue indicator will not appear in the window.

Figure 5.1 Figure 5.2

Step 6

• Hold the skin between two fingers to create a skin fold at the selected, disinfected site (Step 4).
• Hold the syringe in the other hand as shown in Figure 6.1.
• Firmly and in one continuous motion, insert the needle of the pre-filled syringe into the skin fold at an almost vertical position. Insert the needle until the shield fully retracts! See Figure 6.2.

Figure 6.1 Figure 6.2

• While maintaining steady pressure of the syringe against the skin, slowly depress the plunger until the entire solution has been injected under the skin (see Figure 6.3).

Figure 6.3

Step 7

• After administration of the medicine, the blue indicator disappears from the window, confirming the automatic closure of the safety mechanism. The needle shield is activated and protects against needlestick injury (see Figure 7).

Figure 7

• Press an alcohol swab against the injection site until bleeding stops. Do not rub the skin to avoid irritation at the injection site.
• Dispose of the used syringe and needle in a special container designed for this purpose.