Package Insert: Information for the User

Methofill 27.5 mg/0.55 ml Injectable Solution in Preloaded Syringe EFG

Methotrexate

Read this package insert carefully before starting to use the medication, as it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed only for you and should not be given to others, even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

1. What is Methofill and how is it used

2. What you need to know before starting to use Methofill

3. How to use Methofill

4. Possible adverse effects

5. Storage of Methofill

6. Contents of the package and additional information

Methofillcontains methotrexate as the active ingredient.

Methotrexate is a substance with the following properties:

• interferes with the growth of certain cells in the body that reproduce quickly,
• reduces the activity of the immune system (the body's defense mechanism),
• has anti-inflammatory effects.

Methofillis indicated for the treatment of:

• active rheumatoid arthritis in adult patients,
• polyarticular forms of juvenile idiopathic arthritis in active severe form, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has not been adequate,
• severe and incapacitating psoriasis that does not respond adequately to other treatments such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients,
• mild to moderate Crohn's disease in adult patients when it is not possible to use other medications appropriately.

Rheumatoid arthritis (RA) is a chronic collagen disease characterized by inflammation of the synovial membranes (joint membranes). These membranes produce a liquid that acts as a lubricant in many joints. Inflammation causes the membrane to thicken and the joint to swell.

Psoriatic arthritis is a type of arthritis with psoriatic lesions on the skin and nails, especially in the joints of the fingers of the hands and feet.

Poriasis is a chronic and frequent skin disease characterized by red patches covered with thick, dry, silver, and adherent scales.

Methofillmodifies and slows 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.

No use Methofill

• If you are allergic to methotrexate or any of the other components of this medication (listed in section 6),
• if you have severe liver or kidney disease or blood disorders,
• if you regularly consume large amounts of alcohol,
• if you have a severe infection, for example tuberculosis, HIV or other immunodeficiency syndromes,
• if you have mouth ulcers, gastric ulcers or intestinal ulcers,
• if you are pregnant or breastfeeding (see section "Pregnancy, breastfeeding and fertility"),
• if you are receiving vaccines made with attenuated microorganisms at the same time.

Warnings and precautions

Methotrexate can make your skin more sensitive to sunlight. Avoid intense sunlight and do not use sunbeds or ultraviolet lamps without medical advice. To protect your skin from intense sunlight, wear suitable clothing or use a high-protection sunscreen.

Consult your doctor or pharmacist before starting to use Methofill if:

• you are elderly or generally feel unwell and weak,
• you have altered liver function,
• you have dehydration (loss of fluids) problems.

Special precautions for Methofill treatment

Methotrexate temporarily affects the production of sperm and eggs, which is reversible in most cases. Methotrexate can cause severe birth defects and miscarriages. If you are a woman, do not become pregnant while taking methotrexate and for at least 6 months after stopping treatment. If you are a man, do not father a child while taking methotrexate and for at least 3 months after stopping treatment. See also section "Pregnancy, breastfeeding and fertility".

Recommended follow-up tests and safety measures:

Even when Methofill is administered at low doses, severe adverse effects can occur. To detect them in time, your doctor will need to perform blood tests and checks.

Before starting Methofill treatment:

Before starting treatment, you will have blood tests to check that you have enough blood cells, and tests will be performed to check liver function and see if you have hepatitis. In addition, your albumin serum concentration (a blood protein) will be checked, as well as your liver status (infection of the liver) and kidney function. Your doctor may also decide to perform other liver tests, some of which may be images of your liver and others may require a small sample of liver tissue to examine it more closely. Your doctor will also check if you have tuberculosis (an infectious disease with small nodules in the affected tissue) and will perform a chest X-ray or a lung function test.

During treatment:

Your doctor will perform the following tests:

• oral cavity and pharynx examination to detect changes in the mucous membrane, such as inflammation or ulceration blood test;
• blood count with number of blood cells and measurement of methotrexate serum levels;
• blood test to control liver function;
• imaging tests to control liver status;
• small sample of liver tissue taken for closer examination;
• blood test to control kidney function;
• review of the respiratory system and, if necessary, lung function test;

It is very important to attend these scheduled tests.

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

Pulmonary hemorrhage has been reported with methotrexate in patients with underlying rheumatological disease. If you notice blood when coughing or spitting, you should contact your doctor immediately.

Methotrexate can affect the immune system and vaccine results. It can also affect the results of immunological tests. It can intensify chronic inactive infections (e.g., herpes zoster, tuberculosis, hepatitis B or C). During Methofill treatment, do not receive vaccines made with attenuated microorganisms.

During methotrexate treatment, dermatitis caused by radiation and sunburn (memory reactions) can occur. Psoriatic lesions can worsen during UV radiation and simultaneous methotrexate administration.

Lymph node enlargement (lymphoma) can occur, and treatment should be suspended in this case.

Diarrea can be a toxic effect of Methofill that requires suspension of treatment. If you have diarrhea, talk to your doctor.

Certain brain disorders (encephalopathy/leucoencephalopathy) have been reported in cancer patients treated with methotrexate. It cannot be ruled out that these adverse effects may occur when methotrexate is used to treat other diseases.

If you, your partner or caregiver notice the appearance or worsening of neurological symptoms, such as general muscle weakness, visual disturbances, changes in thought, memory and orientation that cause confusion and changes in personality, contact your doctor immediately, as these may be symptoms of a rare and severe brain infection called progressive multifocal leukoencephalopathy (PML).

Older patients

Older patients taking methotrexate should be closely monitored by a doctor to detect any possible side effects as soon as possible.

The deterioration of liver and kidney function related to age, as well as low body reserves of folic acid in the elderly, require a relatively low dose of methotrexate.

Other medications and Methofill

Inform your doctor or pharmacist if you are using, have used recently or may need to use any other medication.Also, take this into account for medications you may take in the future.

The effect of treatment may be affected if Methofill is administered at the same time as certain medications:

• Antibioticssuch as: tetracyclines, chloramphenicol, non-absorbable broad-spectrum antibiotics, penicillins, glucopetides, sulfonamides, ciprofloxacin and cefalotin (medications to prevent or combat certain infections).
• Amoxicillin(penicillins may reduce methotrexate excretion, causing a potential increase in side effects).
• Non-steroidal anti-inflammatory drugsor salicylates (pain or inflammation medications such as aspirin, diclofenac and ibuprofen or pyrazolones)
• Probenecid(a medication for gout).
• Weak organic acids such asdiureticsof the loop
• Medications that can cause adverse effects on thebone marrow, for example trimethoprim-sulfamethoxazole (an antibiotic) and pyrimethamine
• Othermedications used to treat rheumatoid arthritissuch as leflunomide, sulfasalazine and azathioprine.
• Mercaptopurine (achemotherapeutic).
• Retinoids (medications forpsoriasisand other skin diseases)
• Theophylline (medication forasthmaand other lung diseases)
• Some medications forstomach discomfortsuch as omeprazole and pantoprazole.
• Hypoglycemics (medications used toreduce blood sugar levels).
• Metamizole (synonyms novaminsulfon and dipirona)(medication for intense pain and/or fever);

Vitamins containingfolic acidmay alter the effect of your treatment and will only be taken when advised by your doctor.

Do not vaccinate with vaccines made with attenuated microorganisms.

Use of Methofill with food, drinks and alcohol

During Methofill treatment, avoid consuming alcohol, and large amounts of coffee, fizzy drinks containing caffeine and black tea.

Pregnancy, breastfeeding and fertility

Pregnancy

Do not use Methofill during pregnancy or if you are planning to become pregnant. Methotrexate can cause birth defects, harm the fetus or cause miscarriages. It is associated with skull, face, heart and blood vessel malformations, brain and limb malformations. Therefore, it is very important that methotrexate not be administered to pregnant patients or those planning to become pregnant. In fertile women, any possibility of pregnancy should be excluded with appropriate measures, for example, a pregnancy test before starting treatment. You should avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment, using reliable contraceptive methods during this entire time (see also section "Warnings and precautions").

If you become pregnant during treatment or suspect you may be pregnant, consult your doctor as soon as possible. You will be offered information on the risk of harm to the child during treatment.

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

Breastfeeding

Stop breastfeeding before and during Methofill treatment.

Male fertility

The available data do not indicate a higher risk of malformations or miscarriages if the father takes a methotrexate dose of less than 30 mg/week. However, this risk cannot be completely ruled out. Methotrexate can be genotoxic, meaning it can cause genetic mutations. Methotrexate can affect sperm production and cause birth defects. Therefore, you should avoid fathering a child or donating semen while taking methotrexate and for at least 3 months after stopping treatment.

Driving and operating machinery

Methofill treatment can cause adverse reactions affecting the central nervous system, such as fatigue and dizziness. Therefore, your ability to drive or operate machinery may be affected in some cases. If you feel tired or drowsy, do not drive or operate machinery.

Methofill contains sodium

This medication contains less than 23 mg of sodium (1 mmol) per dose; that is, it is essentially "sodium-free".

Follow exactly the administration instructions of this medication as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Your doctor will determine the dosage, which will be adjusted individually. Normally, treatment takes between 4 and 8 weeks to take effect.

The Methofill injection will be administered or supervised by your doctor or healthcare professionalonly once a weekon a day chosen by you and your doctor.Methofill can be injected subcutaneously (under the skin).

At the beginning of treatment, Methofill may be injected by medical personnel. However, your doctor may decide that you can learn to inject Methofill yourself. You will receive the necessary training for this. Under no circumstances should you attempt to inject yourself with Methofill unless you have been taught how to do so.

Use in children and adolescents

Due to the very limited data on the intravenous administration of the medication in children and adolescents, it should only be administered subcutaneously (under the skin).

Your doctor will determine the appropriate dose for children and adolescents with polyarticular forms of juvenile idiopathic arthritis.

Methofill is not recommended for use in children under 3 years of age due to limited experience in this age group.

Duration and administration form

Methofill is injectedonce a week.

Your doctor will decide on the duration of treatment. The treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis, and Crohn's disease with Methofill is a long-term treatment.

At the beginning of treatment, Methofill may be injected by medical personnel. In certain cases, your doctor may decide to teach you how to inject Methofill yourself under the skin. If so, you will receive the necessary training. Under no circumstances should you attempt to inject yourself with Methofill unless you have received this training.

See the usage instructions at the end of the prospectus.

The handling and disposal of the product will be done in accordance with the guidelines for other cytotoxic preparations in accordance with local regulations. Pregnant healthcare personnel should not handle or administer Methofill.

Methotrexate should not come into contact with the skin surface or mucous membranes. If it does, the affected area should be immediately rinsed with plenty of water.

If you use more Methofill than you should

If you use more Methofill than you should, consult your doctor immediately.

If you forget to use Methofill

Do not take a double dose to compensate for the missed doses.

If you interrupt treatment with Methofill

If you interrupt treatment with Methofill, consult your doctor immediately

If you feel that the effect of Methofill is too strong or too weak, consult your doctor or pharmacist.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

The frequency and severity of side effects will depend on the dose and frequency of administration. It is essential that your doctor performs regular check-ups, as severe side effects can occur even with low doses. Your doctor will performtests to monitor abnormalitiesthat may occur in the blood (such as low white blood cell counts, low platelet counts, and lymphoma) and changes in the kidneys and liver.

Inform your doctor immediatelyif you experience any of the following symptoms, as they may indicate a severe side effect or a potentially life-threatening condition that may require urgent specific treatment:

• dry cough, difficulty breathing, and fever;these may be signs of lung inflammation [frequent]
• coughing up blood or blood in sputum; these may be signs of pulmonary hemorrhage [unknown frequency]
• signs of liver damage, such as yellowing of the skin or eyes; methotrexate can cause chronic liver damage (cirrhosis), formation of scar tissue in the liver (hepatic fibrosis), fatty liver degeneration [all rare], acute hepatitis [rare], and liver failure [very rare]
• allergic symptoms, such as skin rash, including itching and redness, swelling of the hands, feet, ankles, face, lips, mouth, and throat (which may cause difficulty swallowing or breathing) and feeling dizzy;these may be signs of severe allergic reactions or anaphylactic shock [rare]
• signs of kidney damage, such as inflammation of the hands, ankles, or feet, or changes in urination frequency or decrease (oliguria) or absence (anuria) of urine;these may be signs of renal failure [rare]
• infection symptoms, such as fever, chills, muscle pain, sore throat;methotrexate may make you more susceptible to infections. Severe infections, such as Pneumocystis jirovecii pneumonia or sepsis [rare], may occur
• symptoms such as weakness on one side of the body (stroke) or pain, swelling, redness, and heat in one leg (deep vein thrombosis); this can happen when a blood clot dislodged causes a blockage of a blood vessel(thromboembolic event) [rare]
• fever and severe deterioration of your general condition, or sudden fever accompanied by sore throat or mouth, or urinary problems;methotrexate can cause a sudden drop in the number of certain white blood cells (agranulocytosis) and severe myelosuppression [very rare].
• unexpected bleeding, e.g., bleeding gums, blood in urine, vomiting with blood, or bruises;these may be signs of severe thrombocytopenia caused by severe episodes of bone marrow depression [very rare]
• symptoms such as severe headache often accompanied by fever, neck stiffness, nausea, vomiting, disorientation, and light sensitivity;these may indicate acute aseptic meningitis [very rare]
• cases of certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients treated with methotrexate; these side effects cannot be ruled out when methotrexate is used to treat other diseases; the signs of this type of brain disorder may bemental state alteration, movement disorders (ataxia), visual disorders, or memory disorders[unknown frequency]

severe skin rash or appearance of blisters on the skin (this can also affect your mouth, eyes, and genitals); these may be signs of a condition called Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell syndrome) [very rare]

Below, you can find other side effects that may occur:

Very frequent:may affect more than 1 in 10 people

• inflammation of the oral mucosa, indigestion, nausea, loss of appetite, abdominal pain.
• abnormal results in liver function tests (ASAT, ALAT, bilirubin, alkaline phosphatase.

Frequent:may affect up to 1 in 10 people

• mouth ulcers, diarrhea.
• skin rash, redness of the skin, itching.
• headache, fatigue, drowsiness.
• decrease in the formation of blood cells with a decrease in the number of white blood cells, red blood cells, or platelets

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

• inflammation of the gum tissue.
• increase in skin pigmentation, acne, bruises on the skin due to blood vessel hemorrhage (ecchymosis, petechiae), allergic inflammation of blood vessels.
• decrease in the number of antibodies in the blood.
• infection (including reactivation of chronic inactive infections), red eyes (conjunctivitis).
• mood changes (mood alterations).
• visual disorders.
• inflammation of the sac surrounding the heart, accumulation of fluid in the sac surrounding the heart, obstruction of cardiac filling due to the presence of fluid in the sac surrounding the heart.
• low blood pressure.
• formation of scar tissue in the lungs (pulmonary fibrosis), difficulty breathing, and asthma, accumulation of fluid in the sac surrounding the lung.
• stress fracture.
• electrolyte imbalances.
• fever, alterations in wound healing.

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

• acute toxic dilation of the intestine (toxic megacolon).
• increase in nail pigmentation, acute inflammation of the cuticles (paronychia), deep infection of hair follicles (furunculosis), visible enlargement of small blood vessels.
• local lesion at the site of administration (formation of sterile abscesses, changes in fatty tissue) after intramuscular injection or subcutaneous injection.
• pain, loss of strength or numbness or tingling/sensitivity to minor stimuli, alterations in taste (metallic taste), convulsions, paralysis, meningism.
• vision alteration, non-inflammatory eye disorder (retinopathy).
• loss of appetite, impotence, increased male breast tissue, altered sperm formation (oligospermia), menstrual disorders, vaginal discharge.
• enlargement of lymph nodes (lymphoma).
• lymphoproliferative disorders (excessive increase in white blood cells).

Unknown frequency:cannot be estimated from available data

• increase in certain white blood cells.
• nosebleed.
• protein in the urine.
• feeling weak.
• jawbone fractures (secondary to excessive increase in white blood cells).
• destruction of tissue at the injection site.
• redness and peeling of the skin.
• swelling

When administered intramuscularly, methotrexate may cause frequent local side effects (burning sensation) or lesions (formation of sterile abscesses, destruction of fatty tissue) at the injection site. Subcutaneous administration of methotrexate is well tolerated locally. Only mild local skin reactions were observed, which decreased during treatment.

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Store below 30 °C.

Store preloaded syringes in the outer packaging to protect them from light.

Do not use this medication after the expiration date shown on the packaging. The expiration date is the last day of the month indicated.

Medicines should not be disposed of through drains or in the trash. Dispose of packaging and unused medications at the SIGRE collection point at the pharmacy. Ask your pharmacist how to dispose of packaging and unused medications. By doing so, you will help protect the environment.

Composition of Methofill

• The active ingredient is methotrexate. 1 ml of solution contains methotrexate disodium corresponding to 50 mg of methotrexate.
• The other components are sodium chloride, sodium hydroxide, water for injection.

Aspect of the product and content of the package

Methofill pre-filled syringes contain a yellow-brown transparent solution. Pre-filled syringes with safety needle guard. The package contains the pre-filled syringe with blister packaging and an alcohol-impregnated gauze.

The following package sizes are available:

Pre-filled syringes containing 0.15 ml, 0.20 ml, 0.25 ml, 0.30 ml, 0.35 ml, 0.40 ml, 0.45 ml, 0.50 ml, 0.55 ml, and 0.60 ml of injectable solution are available in packages of 1 or 4 pre-filled syringes, with subcutaneous injection needles attached, covered with rigid and graduated needle protectors. Additionally, pre-filled syringes with safety needle guard are available.

Only some package sizes may be available.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization:

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est 6th floor,

08039 Barcelona,

Spain

Responsible for manufacturing:

Accord Healthcare B.V.

Winthontlaan 200,

Utrecht, 3526KV

Netherlands

or

Fundació DAU Laboratory

C/ C, 12-14 Pol. Ind. Zona Franca,

Barcelona, Spain

Local Representative:

Rubió Laboratories, S.A.

Industry 29

Polígono Industria Comte de Sert

08755 Castellbisbal

(Barcelona)

Spain

Last review date of this leaflet: August 2024

The detailed and updated information of this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) http://www.aemps.es

Instructions for use

Read carefully the instructions before starting to administer the injection, and always use the recommended application technique advised by your doctor, nurse or pharmacist.

If you have any problems or questions, contact your doctor, nurse or pharmacist.

Preparation

Select a clean, flat, and well-lit work surface.

Wash your hands thoroughly. Before using it, inspect the methotrexate syringe for visible defects (or cracks).

Injection site

Injecting the solution

1. Open the package containing the methotrexate pre-filled syringe and read the leaflet carefully. Remove the pre-filled syringe from the package at room temperature.

Methotrexate should not come into contact with the skin surface or mucous membranes. In case of contamination, the affected area should be washed immediately with plenty of water.

If you or someone in your environment are injured with the needle, consult your doctor immediately and do not use this pre-filled syringe.

Disposal and other manipulations

The manipulation and disposal of the medicine and the pre-filled syringe will be carried out in accordance with local regulations. Pregnant healthcare personnel should not handle or administer methotrexate.