Tullex

Leaflet accompanying the packaging: information for the user

Tullex, 5 mg, solution for injection in a pre-filled syringe

Tullex, 7.5 mg, solution for injection in a pre-filled syringe

Tullex, 10 mg, solution for injection in a pre-filled syringe

Tullex, 12.5 mg, solution for injection in a pre-filled syringe

Tullex, 15 mg, solution for injection in a pre-filled syringe

Tullex, 17.5 mg, solution for injection in a pre-filled syringe

Tullex, 20 mg, solution for injection in a pre-filled syringe

Tullex, 22.5 mg, solution for injection in a pre-filled syringe

Tullex, 25 mg, solution for injection in a pre-filled syringe

Tullex, 27.5 mg, solution for injection in a pre-filled syringe

Tullex, 30 mg, solution for injection in a pre-filled syringe

Methotrexate

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor or pharmacist.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm them, even if their symptoms are the same as yours.
• If the patient experiences any side effects, including any not listed in this leaflet, they should tell their doctor or pharmacist. See section 4.

Table of contents of the leaflet

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

1. What is Tullex solution for injection and what is it used for

Methotrexate is a substance with the following properties:

• slows down the growth of certain cells in the body that divide quickly;
• reduces the activity of the immune system (the body's defense mechanism);
• has anti-inflammatory effects.

Indications for use of Tullex solution for injection:

• active rheumatoid arthritis in adult patients;
• polyarticular forms of severe, active juvenile idiopathic arthritis, if the response to non-steroidal anti-inflammatory drugs is insufficient;
• severe, refractory, disabling psoriasis, in which a satisfactory response has not been achieved with phototherapy, PUVA therapy, and retinoids, and severe psoriatic arthritis in adult patients;
• Crohn's disease with a mild to moderate course in adult patients, when treatment with other drugs is not possible.

Rheumatoid arthritis (RA) is a chronic disease classified as collagenosis, characterized by inflammation of the synovial membranes lining the joints. The synovial membranes produce fluid that acts as a lubricant for many joints. Inflammation causes thickening of the membranes and swelling of the joints.
Juvenile arthritis occurs in children and adolescents under the age of 16. The polyarticular form is indicated by the involvement of 5 or more joints within the first 6 months of the disease.
Psoriatic arthritis is a type of arthritis with psoriatic changes on the skin and nails, particularly affecting the joints of the fingers and toes.
Psoriasis is a common chronic skin disease characterized by red patches covered with thick, dry, silvery, tightly adhering scales.
Tullex solution for injection modifies and slows down the progression of the disease.
Crohn's disease is a type of inflammatory bowel disease that can affect any part of the gastrointestinal tract, causing symptoms such as abdominal pain, diarrhea, vomiting, or weight loss.

2. Important information before using Tullex solution for injection

If the patient, their partner, or caregiver notices a new onset or worsening of neurological symptoms, including general muscle weakness, vision disturbances, changes in thinking, memory, and orientation leading to confusion and personality changes, they should immediately contact their doctor, as these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

When not to use Tullex solution for injection

• if the patient is allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6);
• if the patient has severe liver or kidney disease, or blood disorders;
• if the patient regularly consumes large amounts of alcohol;
• if the patient has a severe infection, such as tuberculosis, HIV infection, or other immunodeficiency syndromes;
• if the patient has oral ulcers, stomach ulcers, or intestinal ulcers;
• if the patient is pregnant or breastfeeding (see "Pregnancy, breastfeeding, and fertility");
• if the patient is receiving a vaccine containing live microorganisms at the same time.

Warnings and precautions

Before starting treatment with Tullex solution for injection, the patient should discuss the following with their doctor or pharmacist:

• if the patient is elderly, frail, or in poor general health;
• if the patient has liver function disorders;
• if the patient has been diagnosed with dehydration (lack of water in the body).

During treatment with methotrexate, cases of acute pulmonary hemorrhage have been reported in patients with underlying rheumatologic disease. If the patient experiences hemoptysis (coughing up blood), they should immediately consult their doctor.
Recommended tests and safety measures
Severe side effects may occur even after administration of low doses of Tullex solution for injection. To detect them early, the doctor must perform regular check-ups and laboratory tests.
Before starting therapy
Before starting treatment, the patient's blood will be tested to check if they have a sufficient number of blood cells. The blood will also be tested to check liver function and detect any liver inflammation. Additionally, serum albumin (a protein in the blood), liver inflammation, and kidney function will be checked.
The doctor may also decide to perform other liver tests, some of which may be imaging tests of the liver, and others may require a small tissue sample taken from the liver for further examination. The doctor may also check for tuberculosis and may take a chest X-ray or perform a lung function test.
During treatment
The doctor may perform the following tests:

• examination of the mouth and throat for changes in the mucous membranes such as inflammation or ulcers
• blood tests/blood morphology with blood cell count and measurement of methotrexate concentration in serum
• blood tests to monitor liver function
• imaging tests to monitor liver condition
• taking a small tissue sample from the liver for further examination
• blood tests to monitor kidney function
• monitoring of the respiratory system and, if necessary, lung function tests

It is very important for the patient to attend these scheduled tests.
If the results of any of these tests draw the doctor's attention, the doctor will adjust the treatment accordingly.
Elderly patients
Elderly patients treated with methotrexate should be closely monitored by their doctor to detect any potential side effects as early as possible.
Age-related disorders of liver and kidney function, as well as low reserves of a vitamin called folic acid in the body, require relatively low doses of methotrexate.
Methotrexate may affect the immune system, vaccination results, and immunological test results. It may lead to the reactivation of latent chronic diseases (e.g., shingles, tuberculosis, hepatitis B or C). During treatment with Tullex solution for injection, vaccines containing live microorganisms should not be used.
Methotrexate may increase skin sensitivity to sunlight. The patient should avoid intense sun exposure and not use a sunbed or tanning lamp without consulting their doctor. To protect the skin from intense sunlight, the patient should wear appropriate clothing or use a sunscreen with a high protection factor.
During treatment with methotrexate, radiation-induced skin inflammation and sunburn (recall reaction) may occur. Exposure to UV radiation during methotrexate treatment may exacerbate psoriatic lesions.
Lymph node enlargement (lymphoma) may occur. In such cases, treatment should be discontinued.
Diarrhea may be a sign of toxic effects of Tullex solution for injection and requires discontinuation of treatment. If the patient experiences diarrhea, they should tell their doctor.
In patients with cancer receiving methotrexate treatment, cases of encephalopathy (brain disease) and leukoencephalopathy (a specific brain disease affecting white matter) have been reported. It is not possible to exclude the occurrence of such side effects in the case of using methotrexate to treat other diseases.
Special precautions for use of Tullex solution for injection
Methotrexate temporarily disrupts the production of sperm and egg cells; in most cases, this effect disappears. Methotrexate may cause miscarriage and severe birth defects. Female patients should avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment. Male patients should avoid impregnating their partner and should not donate sperm while taking methotrexate and for at least 3 months after stopping treatment. See also "Pregnancy, breastfeeding, and fertility".

Children

Tullex solution for injection should not be used in children under the age of 3 due to insufficient experience with the use of methotrexate in this age group.

Tullex solution for injection and other medicines

The patient should tell their doctor or pharmacist about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take.
Concomitant use of certain medicines may affect the action of Tullex solution for injection

• medicines that damage the liver or reduce blood cell count, such as leflunomide;
• antibiotics (e.g., tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics), penicillins, glycopeptides, sulfonamides (sulfur-containing antibiotics), ciprofloxacin, and cefalotin;
• non-steroidal anti-inflammatory drugs or salicylates (pain-relieving and/or anti-inflammatory medicines);
• probenecid (used to treat gout);
• weak organic acids such as loop diuretics (diuretics) or certain pain-relieving and anti-inflammatory medicines (e.g., acetylsalicylic acid, diclofenac, and ibuprofen) and pyrazoles (used to treat pain);
• metamizole (synonyms: novaminsulfone and dipyrone) (a strong pain-relieving and/or antipyretic medicine)
• medicines that may harm bone marrow function, such as trimethoprim-sulfamethoxazole (an antibiotic) or pyrimethamine;
• other medicines used to treat rheumatoid arthritis, such as penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, and cyclosporine;
• mercaptopurine (a cytostatic medicine);
• retinoids (medicines used to treat psoriasis and other skin diseases);
• theophylline (a medicine used to treat asthma and other lung diseases);
• proton pump inhibitors (medicines used to treat stomach diseases);
• medicines that lower blood sugar levels.

Vitamin products containing folic acid or folinic acid should only be used if prescribed by a doctor, as they may reduce the effect of methotrexate.
During treatment with Tullex solution for injection, vaccines containing live microorganisms should not be used.

Tullex solution for injection with food, drink, and alcohol

While using Tullex solution for injection, the patient should avoid drinking alcohol and large amounts of coffee, caffeine-containing beverages, and black tea.

Pregnancy, breastfeeding, and fertility

If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor or pharmacist before using this medicine.
Pregnancy
Do not use Tullex solution for injection if the patient is pregnant or trying to become pregnant. Methotrexate may cause birth defects, 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 female patients who are pregnant or planning to become pregnant do not take methotrexate. If the patient is of childbearing age, it is essential to confirm that they are not pregnant before starting treatment, by taking appropriate measures, such as a pregnancy test. The patient should avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment, using reliable contraception methods throughout this time (see also "Warnings and precautions").
If the patient becomes pregnant while taking methotrexate or suspects they may be pregnant, they should consult their doctor as soon as possible. The patient should receive advice on the potential harmful effects of treatment on the child.
If the patient plans to become pregnant, they should consult their doctor, who may refer them to a specialist for advice before starting treatment.
Breastfeeding
Breastfeeding should be discontinued before starting and during treatment with Tullex solution for injection.
Male fertility
Available data do not indicate an increased risk of birth defects or miscarriages after the father has taken methotrexate at a dose below 30 mg per week. However, it is not possible to completely exclude the risk. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm and cause birth defects. Therefore, male patients should avoid impregnating their partner and should not donate sperm while taking methotrexate and for at least 3 months after stopping treatment.

Driving and using machines

While using Tullex solution for injection, side effects such as fatigue and dizziness may occur. In this regard, the ability to drive vehicles or operate machinery may be impaired in some cases.
In case of drowsiness or fatigue, the patient should not drive or operate machinery.

Tullex solution for injection contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per dose, which means it is considered "sodium-free".

3. How to use Tullex solution for injection

Important warning regarding dosing of Tullex (methotrexate)

In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, and Crohn's disease, Tullex should be used only once a week. Using more Tullex (methotrexate) than prescribed may be fatal. The patient should read section 3 of this leaflet carefully. If they have any questions, they should consult their doctor or pharmacist before taking this medicine.
This medicine should always be used exactly as prescribed by their doctor or pharmacist. The patient should carefully follow the instructions at the end of this leaflet. If they have any doubts, they should consult their doctor or pharmacist.
Tullex solution for injection should be administered by a doctor or healthcare professional, or under their supervision, in injections only once a week. The day of injection should be determined by the patient together with their doctor. Tullex solution for injection can be injected subcutaneously (under the skin).
The doctor will decide on the appropriate dose for children and adolescents with polyarticular forms of juvenile idiopathic arthritis.

Use in children

Tullex solution for injection should not be used in children under the age of 3 due to insufficient experience with the use of this medicine in this age group.
Method and time of administration
Tullex solution for injection is injected once a week!
The treatment duration is determined by the doctor. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, and Crohn's disease with Tullex solution for injection is long-term.
Initially, the doctor may administer the injection. However, the doctor may decide that the patient is able to learn how to self-inject Tullex solution for injection. The patient will be properly trained in this regard. The patient should never attempt to self-inject without prior training.
Handling and disposal of the medicine must be in accordance with the guidelines for handling cytotoxic medicines and local regulations. Female healthcare workers who are pregnant should not handle or administer Tullex solution for injection.
Avoid contact between methotrexate and skin or mucous membranes. In case of contamination, the affected area should be rinsed immediately with plenty of water.
If the patient feels that the effect of Tullex solution for injection is too strong or too weak, they should consult their doctor or pharmacist.

Using more than the recommended dose of Tullex solution for injection

The patient should use the dose prescribed by their doctor. They should not change the dose on their own.
If it is suspected that the patient has used too much Tullex solution for injection, they should immediately contact their doctor. The doctor will decide on the treatment to be taken, depending on the severity of the poisoning.

Missing a dose of Tullex solution for injection

The patient should not take a double dose to make up for a missed dose.
They should take the dose prescribed by their doctor as soon as possible and continue treatment in subsequent weeks.

Stopping treatment with Tullex solution for injection

The patient should not stop or discontinue treatment with Tullex solution for injection without consulting their doctor. If they suspect severe side effects, they should immediately seek medical advice.
If they have any further doubts about using this medicine, they should consult their doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The frequency of side effects is defined as follows:
very common
may occur more frequently than 1 in 10 patients
common
may occur with a frequency of no more than 1 in 10 patients
uncommon
may occur with a frequency of no more than 1 in 100 patients
rare
may occur with a frequency of no more than 1 in 1,000 patients
very rare
may occur with a frequency of no more than 1 in 10,000 patients
not known
frequency cannot be estimated from the available data
The frequency and severity of side effects depend on the dose and frequency of administration of the medicine. Since severe side effects may occur even after administration of low doses, regular medical check-ups are necessary. The treating doctor should order tests to rule out abnormalities in blood parameters (e.g., low white blood cell count, platelet count, or anemia) and changes in liver and kidney function.
The patient should immediately tell their doctorif they experience any of the following symptoms, as they may indicate severe, potentially life-threatening side effects that require urgent treatment:

• persistent dry cough without expectoration, shortness of breath, and fever; these may be symptoms of pneumonia [common]
• hemoptysis (coughing up blood);
• symptoms of liver damage, such as yellowing of the skin and whites of the eyes; methotrexate may cause chronic liver damage (liver cirrhosis), scarring of liver tissue (liver fibrosis), fatty liver degeneration [all uncommon], acute liver inflammation (acute hepatitis) [rare], and liver failure [very rare]
• symptoms of an allergic reaction, such as skin rash, including red, itchy skin, swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing) and a feeling of impending fainting; these may be symptoms of severe allergic reactions or anaphylactic shock [rare]
• symptoms of kidney damage, such as swelling of hands, feet, or ankles, or changes in urine frequency or volume (oliguria or anuria); these may be symptoms of kidney failure [rare]
• symptoms of infection, such as fever, chills, pain; methotrexate may increase the risk of infections. Severe infections, such as a specific type of pneumonia (Pneumocystis carinii pneumonia), and sepsis (blood poisoning) may occur [rare]
• severe diarrhea, bloody vomiting, black or tarry stools; these symptoms may indicate rare, severe gastrointestinal complications caused by methotrexate treatment, such as stomach or intestinal ulcers
• symptoms such as weakness on one side of the body (stroke) or pain, swelling, redness, or unusual warmth in one leg (deep vein thrombosis); this may occur if a blood clot blocks a blood vessel (thromboembolic event) [rare]
• fever and severe deterioration of general health or sudden fever, accompanied by sore throat or mouth sores; methotrexate may cause a severe decrease in the number of certain white blood cells (agranulocytosis) and severe bone marrow suppression [very rare]
• unexpected bleeding, such as bleeding gums, blood in urine, vomiting, or black tarry stools; these may be symptoms of a significant decrease in platelet count in the blood due to severe bone marrow suppression [very rare]

Other side effects that may occur:

• very common: mouth inflammation, nausea (vomiting), decreased appetite, increased liver enzyme activity
• common: mouth ulcers, diarrhea, skin rash, redness, itching, headache, feeling tired, drowsiness, decreased production of blood cells with decreased white blood cell count and/or red blood cell count and/or platelet count (leukopenia, anemia, thrombocytopenia)
• uncommon: throat inflammation, intestinal inflammation, vomiting, reactions similar to sunburn due to increased skin sensitivity to sunlight, hair loss, increased number of rheumatoid nodules, shingles, blood vessel inflammation, rash similar to herpes, hives, diabetes onset, dizziness, confusion, depression, decreased serum albumin, decreased blood cell count, inflammation and ulcers of the bladder or vagina, impaired kidney function, urinary disorders, joint pain, muscle pain, osteoporosis (decreased bone mass)
• rare: increased skin pigmentation, acne, blue spots on the skin due to bleeding from blood vessels, allergic blood vessel inflammation, fever, eye redness, infection, slow wound healing, decreased antibody levels in the blood
• very rare: severe bleeding, toxic dilation of the intestine (toxic megacolon), increased pigmentation of the nails, skin inflammation, deep infection of hair follicles (furunculosis), visible enlargement of small blood vessels, impaired vision, pain, loss of muscle strength or feeling of numbness or tingling, changes in taste (metallic taste), seizures, paralysis, severe headache with fever, retinopathy (non-inflammatory eye disease)
• not known: leukoencephalopathy (disease of the white matter of the brain), pulmonary bleeding, skin redness and peeling, swelling, jawbone damage (due to increased white blood cell count)

Subcutaneous administration of methotrexate is locally well-tolerated. Only mild skin reactions have been observed, which decrease during continued treatment.

Reporting side effects

If side effects occur, including any not listed in this leaflet, the patient should tell their doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring, 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
Side effects can also be reported to the marketing authorization holder.
Reporting side effects will help to gather more information on the safety of this medicine.

5. How to store Tullex solution for injection

The medicine should be stored out of sight and reach of children.
Store at a temperature below 25°C. Do not store in the refrigerator and do not freeze.
Store the pre-filled syringe in the outer packaging to protect it from light.
Do not use this medicine after the expiry date stated on the label and carton after "EXP".
The expiry date refers to the last day of the month stated.
Tullex solution for injection is for single use only. Any unused solution should be discarded.
Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicines they no longer use. This will help protect the environment.

6. Contents of the packaging and other information

What Tullex solution for injection contains

• The active substance is methotrexate.
• The other ingredients are sodium chloride, sodium hydroxide, hydrochloric acid, and water for injection.

This medicine contains less than 1 mmol (23 mg) of sodium per 1 ml, which means it is considered "sodium-free".

What Tullex solution for injection looks like and contents of the pack

Tullex solution for injection is a pre-filled syringe containing a clear, yellowish solution without visible particles.
Tullex solution for injection is a pre-filled syringe with a needle and a safety mechanism, available in packs containing 1 pre-filled syringe or 4, 12 pre-filled syringes. The pack includes alcohol swabs.
Not all pack sizes may be marketed.

Marketing authorization holder and manufacturer

Marketing authorization holder

Egis Pharmaceuticals PLC
Keresztúri út 30-38
1106 Budapest
Hungary

Manufacturer

Basic Pharma Manufacturing B.V.
Burgemeester Lemmensstraat 352
6163 JT Geleen
Netherlands

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Netherlands (RMS)
Methotrexaat Basic Pharma 5 mg, oplossing voor injectie in een voorgevulde spuit

• 37.5 mg/ml Methotrexaat Basic Pharma 7.5 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 10 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 12.5 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 15 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 17.5 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 20 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 22.5 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 25 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 27.5 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml Methotrexaat Basic Pharma 30 mg, oplossing voor injectie in een voorgevulde spuit
• 37.5 mg/ml

Poland
Tullex

Date of last revision of the leaflet: 04.09.2024

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Instructions for use

Before starting the injection, the patient should read the instructions. The injection should always be performed as directed by the doctor or pharmacist.
Tullex solution for injection is for single use only. Any unused solution remaining in the pre-filled syringe should be discarded.
The solution should be clear and free of particles.
If the patient has any problems or questions, they should consult their doctor or pharmacist.

Preparation

Prepare a clean, well-lit, flat surface for work.
Before starting, prepare all necessary items:

• one pre-filled syringe of Tullex solution for injection
• one alcohol swab (included in the packaging). Wash hands carefully. Check the pre-filled syringe: check if the syringe or safety mechanism is damaged or if any parts are detached. Make sure the safety mechanism is in the safe position before use. If the pre-filled syringe does not match the following figure, do not use it:

Figure 1: Safety mechanism
If the patient considers the pre-filled syringe unsuitable for use, they should discard it in a container for biologically hazardous (sharp) instruments.

Injection site

The best injection sites are:

• the upper part of the thigh,
• the abdomen, except for the area around the navel.

If someone is helping the patient with the injection, they can also inject into the back of the arm, just below the shoulder.
With each injection, the patient should change the injection site. This will reduce the risk of irritation at the injection site.
The patient should never inject into an area of skin that is painful, bruised, red, hard, or has scars or stretch marks. If the patient has psoriasis, they should try not to inject the medicine directly into raised, thickened, red, or scaly psoriatic lesions.

Injecting the solution

• 1. Remove the pre-filled syringe from the packaging and carefully read the leaflet. Remove the pre-filled syringe from the packaging at room temperature.
• 2. Disinfection

• Choose the injection site and disinfect it with the included alcohol swab. Let the disinfected injection site dry for at least 60 seconds to allow the disinfectant to dry.
• 3. Remove the needle cap. Carefully remove the needle cap by pulling it straight along the line of the needle. Note: Do nottouch the needle of the pre-filled syringe! After removing the needle cap, discard it in a container for biologically hazardous (sharp) instruments.

The patient should avoid contact between methotrexate and skin or mucous membranes. In case of contamination, the affected area should be rinsed immediately with plenty of water.
If the patient or anyone else is injured by the needle, they should immediately consult a doctor and not use that particular pre-filled syringe.

Disposal and preparation of the medicinal product for use

Handling and disposal of the product must be in accordance with the guidelines for handling cytotoxic medicines and local regulations. Female healthcare workers who are pregnant should not handle or administer methotrexate.