Leaflet: information for the user

Methofill Pen 12.5 mg/0.25 ml pre-filled injectable solution in pen EFG

metotrexato

Read this leaflet carefully before you start 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 questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only 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 side effects, consult your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

1. What Methofill Pen is and what it is used for

2. What you need to know before using Methofill Pen

3. How to use Methofill Pen

4. Possible side effects

5. Storage of Methofill Pen

6. Contents of the pack and additional information

This medication is indicated for the treatment of:

• active rheumatoid arthritis in adult patients,
• severe active polyarticular juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has not been adequate,
• moderate to severe psoriasis in adult patients, and severe psoriatic arthritis in adults,
• mild to moderate Crohn's disease in adult patients when an adequate treatment with other medications is not possible.

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

Juvenile arthritis affects children and adolescents under 16 years old. Polyarticular forms are indicated if there is involvement of 5 or more joints in the first 6 months of the disease.

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

Poriatic 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.

This medication modifies and delays 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.

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Do not use Methofill Pen

• 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, such as tuberculosis, HIV, or other immunodeficiency syndromes,
• If you have mouth ulcers, stomach 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 may make your skin more sensitive to sunlight. Avoid intense sunlight and do not use tanning beds 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 this medication if:

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

A severe lung hemorrhage has been reported in patients with underlying rheumatic disease treated with methotrexate. If you notice blood when coughing or spitting, you should contact your doctor immediately.

Special precautions for Methofill Pen treatment

Methotrexate temporarily affects sperm and egg production, which is usually reversible. 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 administered at low doses, severe adverse reactions can occur. To detect them in time, your doctor will need to perform blood tests and checks.

Before starting Methofill Pen treatment:

Before starting treatment, you will have blood tests to check that you have enough blood cells, and tests to check liver function and hepatitis. In addition, your albumin serum concentration (a blood protein), hepatitis status, and kidney function will be checked. Your doctor may also decide to perform other liver tests, some of which may require imaging of your liver and others may require a small sample of liver tissue for closer examination. Your doctor will also check for tuberculosis (an infectious disease with small nodules in the affected tissue) and perform a chest X-ray or 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,
• Complete blood count with cell count and methotrexate serum level measurement,
• Blood test to control liver function,
• Imaging tests to control liver status,
• Small liver tissue sample taken for closer examination,
• Blood test to control kidney function,
• Respiratory system examination and, if necessary, lung function test.

It is very important to attend these scheduled tests.

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

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

During treatment with methotrexate, radiation-induced dermatitis and sunburn (memory reactions) can occur. Psoriatic lesions can intensify during UV radiation and simultaneous methotrexate administration.

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

Diarrea can be an adverse effect of this medication that requires suspension of treatment. If you have diarrhea, consult 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, vision changes, 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 treated with methotrexate should be closely monitored by a doctor to detect any possible adverse 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.

Methofill Pen use with other medications

Inform your doctor or pharmacist if you are taking, have recently taken, or may need to take any other medication.Also, consider this for medications you may take in the future.

The effect of treatment may be affected if this medication 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 can reduce methotrexate excretion, causing a potential increase in adverse 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, such as trimethoprim-sulfamethoxazole (an antibiotic) and pyrimethamine
• Othermedications used to treat rheumatoid arthritissuch as leflunomide, sulfasalazine, and azathioprine.
• Mercaptopurine (achemotherapeuticagent).
• 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).

Metamizol (synonyms novaminsulfon and dipirona)(medication for intense pain and/or fever);

Vitamins containingfolatecan alter the effect of your treatment and should only be taken when advised by your doctor.

Avoid vaccination with vaccines made with attenuated microorganisms.

Methofill Pen use with food, drinks, and alcohol

During treatment with this medication, avoid consuming alcohol, and large amounts of coffee, caffeinated soft drinks, and black tea.

Pregnancy, breastfeeding, and fertility

Pregnancy

Do not use this medication 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 not to administer methotrexate to pregnant patients or those planning to become pregnant. In fertile women, any possibility of pregnancy should be excluded with appropriate measures, such as 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 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 should be offered information about 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.

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medication.

Breastfeeding

Stop breastfeeding before and during treatment with this medication.

Male fertility

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

Treatment with this medication 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 Pen contains sodium

This medication contains less than 23 mg of sodium (1 mmol) per dose; 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 dose, which will be adjusted individually. Normally, the treatment takes between 4 and 8 weeks to take effect.

The injection of this medication is administered subcutaneously (under the skin) under the supervision of a doctor or healthcare professionalonly once a weekon a day chosen by you and your doctor.

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

Use in children and adolescents

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

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

Duration and administration form

This medication 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 this medication is a long-term treatment.

At the beginning of treatment, this medication may be injected by medical personnel. However, your doctor may decide that you can learn to inject this medication yourself. You will receive the necessary training for this.

In no circumstances should you attempt to inject yourself unless you have been taught to do so.

You can also find guidance on how to use this medication in the "Instructions for use" section.

Remember to use the entire contents.

The way to handle and dispose of the medication and the pre-filled pen will be in accordance with local regulations. Pregnant healthcare personnel should not handle or administer this medication.

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

Instructions for use

Recommendations

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

Additional information

The way to handle and dispose of the medication and the pre-filled pen will be in accordance with local regulations. Pregnant healthcare personnel should not handle or administer this medication.

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

What to do before administering your injection

• Choose a clean, flat, and well-lit work surface.
• Check the expiration date. Do not use if the expiration date has passed.
• Take an alcohol-soaked swab and a container for disposing of sharp objects
• Open the box containing the pre-filled methotrexate pen andplace the pre-filled pen on a flat and clean surface (such as a table). Read the leaflet carefully.

How to prepare the injection

How to inject yourself

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.

Who to contact in case of need

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

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

Disposal and other manipulations

The handling and disposal of the medication and the pre-filled pen will be in accordance with local regulations. Pregnant healthcare personnel should not handle or administer methotrexate.

If you use more Methofill Pen than you should

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

If you forget to use Methofill Pen

Do not use a double dose to compensate for the missed dose.

If you interrupt treatment with Methofill Pen

If you interrupt treatment with this medication, consult your doctor immediately

If you think the effect of this medication is too strong or too weak, consult your doctor or pharmacist.

If you suspect that you (or someone else) has administered too much Methofill Pen, contact your doctor or go to the nearest hospital immediately or consult the Toxicology Information Service, phone 91 562 04 20. They will decide what measures to take based on the severity of the overdose. Bring the medication with you if you go to the doctor or hospital.

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 detect abnormalitiesthat occur in the blood (such as low white blood cell count, low platelet count, or lymphoma) and kidney and liver alterations.

If you experience any of the following symptoms,contact your doctor immediately, as they may indicate a severe, potentially life-threatening side effect that requires urgent specific treatment:

• Persistent dry cough, difficulty breathing, and fever;these may be signs of a lung inflammation [frequent]
• Blood when coughing or sneezing; these may be signs of pulmonary hemorrhage [unknown frequency]
• Symptoms 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 (fibrosis), fatty liver degeneration [all rare], acute hepatitis [rare], and liver failure [very rare]
• Allergic symptoms, such as skin rash, including itching, swelling of hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing) and feeling of fainting;these may be signs of severe allergic reactions or anaphylactic shock [rare]
• Symptoms of kidney damage, such as swelling of hands, ankles, or feet, or changes in urination frequency or decreased (oliguria) or absent (anuria) urine;these may be signs of kidney failure [rare]
• Symptoms of infections, e.g., fever, chills, pain, sore throat;methotrexate may make you more susceptible to infections. Severe infections, such as a specific type of pneumonia (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 pain, 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 hematomas;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]
• 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 blistering of the skin (this can also affect the 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 will find other side effects that may occur:

Very frequent:may affect more than 1 in 10 people

• Oral mucositis, 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.
• Rash, skin redness, itching.
• Headache, fatigue, drowsiness.
• Decreased blood cell formation with decreased white blood cell, red blood cell, or platelet count

Rare:may affect up to 1 in 100 people

• Throat inflammation.
• Intestinal inflammation, vomiting, pancreatitis, black or tar-like stools, ulcers, and bleeding.
• Sunburn-like reactions due to increased skin sensitivity to sunlight, hair loss, increased number of rheumatoid nodules, skin ulcers, herpes zoster, inflammation of blood vessels, herpes-like rash, urticaria.
• Appearance of diabetes mellitus.
• Dizziness, confusion, depression.
• Decreased serum albumin.
• Decreased number of all blood cells and platelets.
• Urinary or vaginal inflammation, decreased kidney function, urinary disorders.
• Joint pain, muscle pain, reduced bone mass.

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

• Periodontal inflammation.
• Increased skin pigmentation, acne, bruising on the skin due to blood vessel hemorrhage (ecchymosis, petechiae), allergic inflammation of blood vessels.
• Decreased number of antibodies in the blood.
• Infection (including reactivation of chronic inactive infections), red eyes (conjunctivitis).
• Mood changes (mood alterations).
• Visual disorders.
• Pericarditis, fluid accumulation in the pericardial sac, cardiac filling obstruction due to fluid accumulation in the pericardial sac.
• Low blood pressure.
• Pulmonary fibrosis, respiratory difficulty, and asthma, fluid accumulation in the pleural sac.
• Stress fracture.
• Electrolyte imbalances.
• Fever, wound healing alterations.

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

• Toxic and acute dilation of the intestine (toxic megacolon).
• Increased nail pigmentation, acute paronychia, deep folliculitis, visible enlargement of small blood vessels.
• Pain, loss of strength, or numbness or tingling/sensitivity to minor stimuli, altered taste (metallic taste), convulsions, paralysis, meningism.
• Visual disturbances, non-inflammatory eye disorders (retinopathy).
• Loss of appetite, impotence, increased male breast tissue, altered sperm formation (oligospermia), menstrual disorders, vaginal discharge.
• Enlarged lymph nodes (lymphoma).
• Lymphoproliferative disorders (excessive increase in white blood cells).

Unknown frequency:cannot be estimated from available data

• Increased number of certain white blood cells.
• Nasal bleeding.
• Proteins in the urine.
• Feeling of weakness.
• Fracture of the jaw bones (secondary to excessive increase in white blood cells).
• Tissue destruction at the injection site.
• Redness and peeling of the skin.
• Swelling.

Subcutaneous administration of methotrexate is well tolerated at the local level. Only mild local skin reactions (such as burning sensations, erythema, swelling, color change, severe itching, pain) 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 throughthe Spanish System for Pharmacovigilance of Medicines for Human Use:awww.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 the preloaded cartridges in the outer packaging to protect them from light.

Do not use this medication after the expiration date that appears on the box and on the preloaded cartridge after CAD. The expiration date is the last day of the month indicated.

Medicines should not be disposed of through the drains or in the trash. Dispose of the containers and medicines you no longer need at the SIGRE collection point of the pharmacy. Ask your pharmacist how to dispose of the containers and medicines you no longer need. By doing so, you will help protect the environment.

Composition of Methofill Pen

• The active ingredient is methotrexate. 1 ml of solution contains methotrexate disodium corresponding to 50 mg of methotrexate.

1 preloaded pen with 0.25 ml of solution contains 12.5 mg of methotrexate

• The other components are sodium chloride, sodium hydroxide for pH adjustment, water for injectable preparations.

Appearance of the product and content of the container

The preloaded pens of Methofill Pen contain a yellow-brown transparent solution. The following container sizes are marketed:

Preloaded 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 containers of 1 or multipacks of 4 (4 packs of 1) preloaded pens.

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 Polska Sp.z.o.o.

ul.Lutomierska 50

pabianice, 95-200

Poland

or

Fundació DAU Laboratory

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

Spain

Local Representative:

Laboratorios Rubió, S.A.

Industria 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