Methofill 12.5 mg/0.25 ml solution for injection in pre-filled syringe EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Methofill 12.5 mg/0.25 ml solution for injection in pre-filled syringe EFG

Methotrexate

Read the entire 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, ask your doctor or pharmacist.
• This medicine has been prescribed for you only and must not be given to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any adverse reactions, talk to your doctor or pharmacist, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

1. What Methofill is and what it is used for
2. What you need to know before using Methofill
3. How to use Methofill
4. Possible side effects
5. How to store Methofill
6. Contents of the pack and other information

1. What Methofill is and what it is used for

Methofill contains methotrexate as the active substance.

Methotrexate is a substance with the following properties:

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

Methofill is indicated for the treatment of:

• active rheumatoid arthritis in adult patients,
• polyarticular forms of active severe juvenile idiopathic arthritis when the response to non-steroidal anti-inflammatory drugs (NSAIDs) has been inadequate,
• severe recalcitrant disabling psoriasis that is not adequately controlled by other therapies such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients,
• mild to moderate Crohn's disease in adult patients when 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 thickening of the membrane and joint swelling.

Juvenile arthritis affects children and adolescents under 16 years of age. Polyarticular forms are defined by involvement of five or more joints within the first six months of the disease.

Psoriatic arthritis is a type of arthritis associated with psoriatic skin and nail lesions, 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, and adherent scales.

Methofill modifies 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.

2. What you need to know before using Methofill

Do not use Methofill

• if you are allergic to methotrexate or to any of the other ingredients of this medicine (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, gastric ulcer or intestinal ulcer,
• if you are pregnant or breastfeeding (see section "Pregnancy, breastfeeding and fertility"),
• if you are receiving vaccines prepared with attenuated microorganisms at the same time.

Warnings and precautions

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

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

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

Special precautionary measures for treatment with Methofill

Methotrexate temporarily affects the production of sperm and ova, which is reversible in most cases. Methotrexate may cause miscarriage and serious birth defects. If you are a woman, you must avoid becoming pregnant while receiving methotrexate and for at least 6 months after stopping treatment with methotrexate. If you are a man, you must avoid fathering a child while receiving methotrexate and for at least 3 months after stopping treatment. See also section "Pregnancy, breastfeeding and fertility".

Follow-up tests and recommended safety measures:

Even when Methofill is administered at low doses, severe adverse effects may occur. To detect them early, your doctor must perform blood tests and check-ups.

Before starting treatment with Methofill:

Before starting treatment, blood tests will be performed to ensure you have sufficient blood cells. Tests will also be carried out to assess liver function and determine whether you have hepatitis. In addition, serum albumin levels (a blood protein), hepatitis status (liver infection), and kidney function will be checked. Your doctor may also decide to perform additional liver tests, some of which may include imaging of your liver and others may require taking a small tissue sample from the liver for closer examination. Your doctor will also check whether you have tuberculosis (an infectious disease associated with small nodules in affected tissue) and will perform a chest X-ray or lung function test.

During treatment:

Your doctor will carry out the following tests:

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

It is very important that you attend these scheduled tests.

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

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

Methotrexate may affect the immune system and vaccination outcomes. It may also affect the results of immunological tests. It may reactivate chronic latent infections (e.g., herpes zoster ["shingles"], tuberculosis, hepatitis B or C). During treatment with Methofill, you must not receive vaccines prepared with attenuated microorganisms.

During treatment with methotrexate, radiation dermatitis and sunburns may reappear (memory reactions). Psoriatic lesions may worsen during UV radiation and concomitant administration of methotrexate.

An increase in the size of lymph nodes (lymphoma) may occur, and in such cases, treatment should be discontinued.

Diarrhea may be a toxic effect of Methofill requiring discontinuation of treatment. If you have diarrhea, speak to your doctor.

Certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients treated with methotrexate. The occurrence of these adverse effects cannot be ruled out when methotrexate is used to treat other diseases.

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

Elderly patients

Elderly patients receiving methotrexate should be closely monitored by a doctor to detect possible side effects as early as possible.

Age-related decline in liver and kidney function, as well as low body stores of folic acid in older age, require a relatively low dose of methotrexate.

Other medicines and Methofill

Inform your doctor or pharmacist if you are taking, have recently taken or might need to take any other medicines. Keep this in mind also for medicines you may take in the future.

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

• Antibiotics such as: tetracyclines, chloramphenicol, non-absorbable broad-spectrum antibiotics, penicillins, glycopeptides, sulfonamides, ciprofloxacin and cephalothin (medicines to prevent or treat certain infections).
• Amoxicillin (penicillins may reduce methotrexate excretion, potentially increasing side effects).
• Non-steroidal anti-inflammatory drugs (NSAIDs) or salicylates (medicines for pain or inflammation such as acetylsalicylic acid, diclofenac and ibuprofen or pyrazolones)
• Probenecid (a medicine for gout).
• Weak organic acids such as loop diuretics
• Medicines that may cause adverse effects on the bone marrow, for example trimethoprim-sulfamethoxazole (an antibiotic) and pyrimethamine
• Other medicines used to treat rheumatoid arthritis such as leflunomide, sulfasalazine and azathioprine.
• Mercaptopurine (a cytostatic).
• Retinoids (medicines for psoriasis and other skin diseases)
• Theophylline (a medicine for bronchial asthma and other lung diseases)
• Some medicines for stomach discomfort such as omeprazole and pantoprazole.
• Hypoglycemics (medicines used to lower blood sugar levels).
• Metamizole (synonyms: novaminsulfone and dipyrone) (a medicine for severe pain and/or fever);

Vitamins containing folic acid may alter the effect of your treatment and should only be taken if advised by your doctor.

Vaccination with vaccines prepared with attenuated microorganisms must be avoided.

Use of Methofill with food, drinks and alcohol

During treatment with Methofill, consumption of alcohol, large amounts of coffee, caffeinated soft drinks and black tea should be avoided.

Pregnancy, breastfeeding and fertility

Pregnancy

Do not use Methofill during pregnancy or if you are trying to become pregnant. Methotrexate may cause birth defects, harm the fetus or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very important that methotrexate is not administered to pregnant patients or those planning to become pregnant. In women of childbearing age, any possibility of pregnancy must be excluded using appropriate measures, for example, a pregnancy test before starting treatment. You must avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment, 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, consult your doctor as soon as possible. You should be provided with information about the risk of harmful effects on the child during treatment.

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

Breastfeeding

Discontinue breastfeeding before and during treatment with Methofill.

Male fertility

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

Driving and use of machines

Treatment with Methofill may cause adverse reactions affecting the central nervous system, such as fatigue and dizziness. Therefore, the ability to drive or operate machinery may, in some cases, be impaired. If you feel tired or drowsy, you should not drive or operate machinery.

Methofill contains sodium

This medicine contains less than 23 mg of sodium (1 mmol) per dose; hence, essentially "sodium-free".

3. How to use Methofill

Follow exactly the instructions for administering this medicine as given by your doctor. If in doubt, consult your doctor or pharmacist again.

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

The Methofill injection will be administered or supervised by your doctor or healthcare professional only once a week. Together with your doctor, you will choose a day of the week suitable for you to receive the injection. Methofill can be injected subcutaneously (under the skin).

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

Important warning about the dose of Methofill (methotrexate): Use Methofill only once a week for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, and Crohn's disease. Overuse of Methofill (methotrexate) can be fatal. Read section 3 of this leaflet very carefully. If you have any doubts, consult your doctor or pharmacist before taking this medicine.

Use in children and adolescents

Due to very limited data on intravenous administration of the medicine in children and adolescents, Methofill should only be administered by subcutaneous injection (under the skin).

The physician will determine the appropriate dose in 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 method of administration

Methofill is injected once weekly.

The treating physician will decide on the duration of treatment. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis, and Crohn's disease with Methofill is intended as a long-term therapy.

At the start of treatment, Methofill may be administered by healthcare professionals. In certain cases, your doctor may decide to teach you how to self-inject Methofill under the skin. If so, you will receive appropriate training.

Under no circumstances should you attempt to self-inject Methofill before receiving such training.

Refer to the instructions for use at the end of this leaflet.

Handling and disposal of the product must be carried out in accordance with guidelines for other cytotoxic preparations, according to local regulations. Pregnant healthcare personnel must not handle or administer Methofill.

Methotrexate must not come into contact with the skin surface or mucous membranes. If contact occurs, the affected area should be immediately rinsed with copious amounts of water.

If you use more Methofill than you should

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

If you forget to use Methofill

Do not take a double dose to make up for a missed dose.

If you stop 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, contact your doctor or pharmacist immediately or call the Toxicology Information Service at telephone number: 91 562 04 20.

4. Possible adverse effects

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

The frequency and severity of adverse effects depend on the dose and frequency of administration. It is important that your doctor performs regular check-ups, as serious adverse effects may occur even with the lowest doses. Your doctor will carry out tests to monitor for abnormalities in your blood (such as low levels of leukocytes (white blood cells), low platelets, and lymphoma), and changes in the kidneys and liver.

Contact your doctor immediately if you experience any of the following symptoms, as they may indicate a serious or potentially life-threatening adverse effect that may require urgent specific treatment:

• Dry, non-productive cough, difficulty breathing, and fever; these may be signs of lung inflammation [common]
• coughing up blood; these may be signs of pulmonary haemorrhage [frequency not known]
• signs of liver damage, such as yellowing of the skin or eyes (jaundice); methotrexate may cause chronic liver damage (cirrhosis), scarring of the liver (hepatic fibrosis), fatty degeneration of the liver [all uncommon], inflammation of the liver (acute hepatitis) [rare], and liver failure [very rare]
• signs of allergy, such as skin rash including itching and redness of the skin, swelling of the hands, feet, ankles, face, lips, mouth and throat (which may cause difficulty swallowing or breathing), and feeling faint; these may be signs of severe allergic reactions or anaphylactic shock [rare]
• signs of kidney damage, such as swelling of the hands, ankles or feet, or changes in the frequency of urination or reduced (oliguria) or absent (anuria) urine output; these may be signs of kidney failure [rare]
• signs of infection, for example fever, chills, muscle aches, sore throat; methotrexate may make you more susceptible to infections. Serious infections may occur, such as a type of pneumonia (Pneumocystis jirovecii pneumonia) or blood infection (sepsis) [rare]
• symptoms such as weakness on one side of the body (stroke) or pain, swelling, redness and unusual warmth in one leg (deep vein thrombosis); this may occur when a dislodged blood clot causes blockage of a blood vessel (thromboembolic event) [rare]
• fever and severe deterioration in your general condition, or sudden fever accompanied by sore throat or mouth pain, or urinary problems; methotrexate may 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 blood, or bruising; these may be signs of a severe decrease in platelet count caused by severe episodes of bone marrow suppression [very rare]
• symptoms such as severe headache, often in combination with fever, neck stiffness, nausea, vomiting, disorientation, and sensitivity to light; these may indicate inflammation of the membranes surrounding the brain (acute aseptic meningitis) [very rare]
• certain brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients treated with methotrexate; these adverse effects cannot be ruled out when methotrexate treatment is used to treat other diseases; signs of such brain disorders may include mental status changes, movement disorders (ataxia), visual disturbances, or memory disorders [frequency not known]
• severe skin rash or development of blisters on the skin (this may also affect your mouth, eyes, and genitals); these may be signs of a condition called Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome) [very rare]

Below are other adverse effects that may occur:

Very common: may affect more than 1 in 10 people

• Inflammation of the lining of the mouth, indigestion, nausea, loss of appetite, abdominal pain.
• Abnormal results in liver function tests (ASAT, ALAT, bilirubin, alkaline phosphatase).

Common: may affect up to 1 in 10 people

• Mouth ulcers, diarrhoea.
• Rash, redness of the skin, itching.
• Headache, fatigue, drowsiness.
• Decreased production of blood cells with reduction in the number of white blood cells, red blood cells, or platelets.

Uncommon: may affect up to 1 in 100 people

• Sore throat.
• Inflammation of the intestine, vomiting, inflammation of the pancreas, black or tarry stools, gastrointestinal ulcers and bleeding.
• Sunburn-like reactions due to increased sensitivity of the skin to sunlight, hair loss, increase in the number of rheumatoid nodules, skin ulcer, shingles (herpes zoster), inflammation of blood vessels, herpes-like rash, urticaria.
• Development of diabetes mellitus.
• Dizziness, confusion, depression.
• Decrease in serum albumin.
• Decrease in the number of all blood cells and platelets.
• Inflammation and ulceration of the urinary bladder or vagina, decreased kidney function, urinary disorders.
• Joint pain, muscle pain, reduced bone mass.

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

• Inflammation of gum tissue.
• Increased skin pigmentation, acne, skin bruising due to bleeding from blood vessels (ecchymosis, petechiae), allergic inflammation of blood vessels.
• Decrease in the number of antibodies in the blood.
• Infection (including reactivation of inactive chronic infections), red eyes (conjunctivitis).
• Mood changes (mood disturbances).
• Visual disturbances.
• Inflammation of the sac surrounding the heart (pericarditis), fluid accumulation in the sac around the heart, obstruction of heart filling due to fluid in the pericardial sac.
• Low blood pressure.
• Scarring of lung tissue (pulmonary fibrosis), difficulty breathing and bronchial asthma, fluid accumulation in the sac surrounding the lung (pleural effusion).
• Stress fracture.
• Electrolyte disturbances.
• Fever, impaired wound healing.

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

• Toxic, acute dilation of the intestine (toxic megacolon).
• Increased pigmentation of the nails, inflammation of the cuticles (acute paronychia), deep infection of hair follicles (furunculosis), visible enlargement of small blood vessels.
• Local injury at the site of administration (formation of sterile abscesses, changes in fatty tissue) after injection into a muscle or under the skin.
• Pain, loss of strength, or sensation of numbness or tingling/reduced sensitivity to stimuli, taste disturbances (metallic taste), seizures, paralysis, meningism.
• Vision changes, non-inflammatory eye disorder (retinopathy).
• Loss of sexual desire, impotence, male breast enlargement, altered sperm formation (oligospermia), menstrual disorders, vaginal discharge.
• Enlargement of lymph nodes (lymphoma).
• Lymphoproliferative disorders (excessive increase in white blood cells).

Frequency not known: cannot be estimated from the available data

• Increase in the number of certain white blood cells.
• Nosebleeds.
• Protein in the urine.
• Feeling of weakness.
• Jaw bone damage (secondary to excessive increase in white blood cells).
• Tissue destruction at the injection site.
• Redness and peeling of the skin.
• Swelling.

When methotrexate is administered intramuscularly, local adverse reactions (such as burning sensation) or lesions (formation of sterile abscesses, destruction of fatty tissue) at the injection site may occur frequently. Subcutaneous administration of methotrexate is well tolerated locally. Only mild local skin reactions have been observed, which decreased during treatment.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via www.notificaRAM.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Methofill

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

Store below 30 ºC.

Keep the pre-filled syringes in the outer packaging to protect them from light.

Do not use this medicine after the expiry date stated on the container. The expiry date is the last day of the month indicated.

Medicines must not be disposed of via wastewater or household waste. Dispose of empty containers and unused medicines at the SIGRE collection point at your pharmacy. Ask your pharmacist how to dispose of containers and medicines you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of Methofill

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

Appearance of the product and contents of the pack

The pre-filled syringes of Methofill contain a yellow-brown transparent solution. Pre-filled syringes are equipped with a fixed needle shield safety device. The pack contains the pre-filled syringe in a blister pack and an alcohol-impregnated swab.

The following pack 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, available in packs of 1 or 4 pre-filled syringes, with attached subcutaneous injection needles covered with rigid needle protectors and graduated. In addition, the pre-filled syringes with fixed needles come with a needle safety shield.

Only certain pack sizes may be commercially available.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder:

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est 6th floor,

08039 Barcelona,

Spain

Manufacturer:

Accord Healthcare Polska Sp.z.o.o.

ul.Lutomierska 50

Pabianice, 95-200

Poland

or

Laboratori Fundació DAU

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

Barcelona, Spain

Date of the most recent revision of this leaflet: August 2024

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.es

Instructions for use

Read the instructions carefully before starting the injection, and always use the administration 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 working surface.

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

Injection site

The best places for injection are: the upper thigh, the abdomen, except for the area around the navel.

If someone is helping you with the injection, they may also administer the injection into the back of the arm, just below the shoulder. Change the injection site each time. This may reduce the risk of developing injection site reactions. Never inject into skin that is painful, bruised, red, hard, scarred, or has stretch marks. If you have psoriasis, do not attempt to inject directly into lesions or raised, thickened, red, or scaly patches of skin.

Solution injection

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

Disinfection	Select an injection site and disinfect it using the alcohol-impregnated gauze. Wait 60 seconds for the disinfectant to dry completely.
Ensure the system is intact/undamaged	Check the integrity of the device. Do not use the device: If any damage is observed (breakage of the syringe or device) or loss of components; If the device is in the safety position before use, as this indicates the system has already been activated. In general, the device cannot be used if it does not match the figure on the left. If so, discard the device in a biohazard container (sharps).
Remove the protective cap	Hold the body of the device in one hand with the needle end pointing away from you, without touching the plunger rod. With the other hand, pull the needle cap straight off; After removal, discard the needle cap into a biohazard container (sharps).
Insert the needle	Gently pinch the skin at the injection site with one hand; With the other hand, insert the needle into the injection site without touching the plunger rod head (e.g., at a 90-degree angle).
Injection	-Place your thumb on the plunger rod head; -Press down on the plunger rod and push firmly until the end of the injection to ensure the syringe is completely emptied. Hold the skin securely until the injection is complete.
Needlestick protection	The safety mechanism will activate once the plunger rod is fully depressed: -Keep the syringe still and slowly lift your thumb from the plunger rod head; -The plunger rod will move upward with your thumb, and the spring will retract the needle from the site into the needle safety shield.
Dispose of the device	Immediately after use, discard the device in a biohazard container (sharps). Do not dispose of used needle safety shields in household waste.

Methotrexate must not come into contact with the skin surface or mucous membranes. In case of contamination, immediately rinse the affected area thoroughly with water.

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

Disposal and other handling

Handling and disposal of the medicinal product and the pre-filled syringe must be carried out in accordance with local regulations. Pregnant healthcare personnel must not handle or administer methotrexate.