Package Insert: Information for the User

IMETH12.5mg/0.5 mlInjectable Solution in Preloaded Syringe

Methotrexate

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

• Keep this package insert, as you may need to refer to it again.

• If you have any questions, consult your doctor or pharmacist.

• This medication has been prescribed to you alone, and you should not give it 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 IMETH and how is it used

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

3. How to use IMETH

4. Possible adverse effects

5. Storage of IMETH

6. Contents of the package and additional information

Imeth is a medication with the following properties:

- Interferes with the growth of certain cells in the body that multiply rapidly (antineoplastic agent).

- Reduces unwanted reactions of the body's own defense mechanism (immunosuppressant).

- Has anti-inflammatory effects.

Imeth is indicated for the treatment of:

- Active rheumatoid arthritis in adult patients.

- Polyarticular forms of juvenile idiopathic arthritis in active and severe cases when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.

- Severe, recalcitrant, and incapacitating psoriasis that does not respond adequately to other forms of treatment such as phototherapy, PUVA, and retinoids, and severe psoriasis that affects the joints (psoriatic arthritis) in adult patients.

- Mild to moderate Crohn's disease in adult patients who are refractory or intolerant to thiopurines.

Important notice regarding the administration of methotrexate:

Methotrexate should only be used once a week for the treatment of rheumatic diseases or skin diseases. Inadequate administration of methotrexate can cause severe adverse effects, including a fatal outcome. Read section 3 of this prospectus carefully.

Ask your doctor or pharmacist if you have any doubts before using Imeth.

Do not useIMETH:

• If you are allergic (hypersensitive) to methotrexate or to any of the other components of this medication (see section 6).
• If you have any significant kidney disease (your doctor decides the severity of the disease).
• If you have any significant liver disease (your doctor decides the severity of your disease).
• If you have hematopoietic system disorders.
• If you have a high alcohol consumption.
• If you have an altered immune system.
• If you have a severe or existing infection; e.g., tuberculosis and HIV.
• If you have gastrointestinal ulcers.
• If you are pregnant or breastfeeding (see section "Pregnancy, lactation and fertility").
• If you are receiving live vaccines at the same time.

Warnings and precautions

Methotrexate has been associated with acute pulmonary hemorrhage in patients with underlying rheumatological disease. If you observe blood when coughing or expectorating, you should contact your doctor immediately.

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 form of brain infection called progressive multifocal leukoencephalopathy (PML).

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-factor sunscreen.

Consult your doctor before starting to use Imeth

• If you have diabetes mellitus treated with insulin.
• If you have chronic inactive infections (e.g., tuberculosis, hepatitis B or C, herpes [herpes zoster]).
• If you have or have had significant liver or kidney disease.
• If you have respiratory problems.
• If you have severe obesity.
• If you have abnormal accumulation of fluid in the abdomen or in the cavity between the lungs and the chest wall (ascitis, pleural effusion).
• If you are dehydrated or have a disorder that may cause dehydration (vomiting, diarrhea, stomatitis).

The treatment should be administeredonce a week.

Inadequate administration of methotrexate can cause severe adverse effects, including potentially fatal effects. Read section 3 of this prospectus carefully.

If you have had skin problems after radiation therapy (radiation-induced dermatitis) and sunburns, these conditions may recur during methotrexate treatment (memory reaction).

Use in children, adolescents and elderly patients

The administration instructions depend on the patient's body weight. The use of Imeth is not recommended in children under 3 years of age due to insufficient experience with this age group.

Children and elderly patients receiving Imeth should undergo frequent medical monitoring to identify potential adverse effects as soon as possible.

A doctor should closely monitor elderly patients receiving methotrexate to detect potential adverse effects as soon as possible.

In elderly patients, in the event of age-related hepatic and renal insufficiency and low folate reserves in the body, a relatively low dose of methotrexate is required.

Special precautions during treatment with Imeth

Imeth should only be prescribed by doctors with sufficient experience in treating methotrexate for the disease in question.

Methotrexate temporarily affects sperm and egg production. Methotrexate can cause severe birth defects and damage to the fetus. If you are a woman, you should avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment. If you are a man, you should avoid fathering a child while taking methotrexate and for at least 3 months after stopping treatment.

See also section "Pregnancy, lactation and fertility".

Psoriasis skin lesions may worsen during Imeth treatment if you are exposed to UV radiation at the same time.

Recommended follow-up examinations and precautions:

Even when used at low doses, methotrexate can cause severe adverse effects. To detect them in time, your doctor will perform follow-up examinations and laboratory tests.

Before starting treatment:

Before starting treatment, a blood test will be performed to determine if you have enough blood cells. You will also have a blood test to check liver function and discover if you have hepatitis. In addition, your albumin serum levels (a blood protein) will be checked, as well as your hepatitis status and renal function. Your doctor may also decide to perform other liver tests, which may include imaging of the liver or taking a small sample of liver tissue for further examination. Your doctor may also check if you have tuberculosis and perform a chest X-ray or a lung function test.

During treatment:

Your doctor may perform the following examinations:

• Oral cavity and pharynx examination to detect changes in the mucosa, such as inflammation or ulcers.
• Blood test/hemogram with blood cell count and measurement of serum methotrexate levels.
• Blood test to control liver function.
• Imaging tests to control liver status.
• Small sample of liver tissue for further examination.
• Blood test to control renal function.
• Respiratory tract examination, and if necessary, lung function test.

It is very important that you attend these scheduled examinations.

If some of these test results are abnormal, your doctor will adjust your treatment accordingly.

Other medications and Imeth

Inform your doctor or pharmacistif you are using,have used recently or may need to use any other medication, including over-the-counter medications and herbal or natural products.

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

• Other treatments for rheumatoid arthritis or psoriasis, such as leflunomide, sulfasalazine (also used for ulcerative colitis), aspirin, phenylbutazone or amidopyrine.
• Alcohol (should be avoided).
• Live vaccines.
• Azathioprine (used to prevent organ transplant rejection).
• Retinoids (used to treat psoriasis and other skin diseases).
• Anticonvulsants (to prevent seizures).
• Cancer treatments.
• Barbiturates (injection for sleep).
• Tranquilizers.
• Oral contraceptives.
• Probenecid (for gout).
• Antibiotics.
• Pirimethamine (used to prevent and treat malaria).
• Vitamin preparations containing folic acid.
• Inhibitors of the proton pump (used to treat severe stomach acid or ulcers).
• Theophylline (used to treat asthma).
• Metamizole (synonyms: novaminsulfon and dipirona) (medication for intense pain and/or fever).

Use ofIMETHwith food, drinks and alcohol

During treatment with Imeth, you should avoid consuming alcohol and excessive amounts of coffee, caffeinated soft drinks and black tea.

Also, make sure to drink a large amount of liquids during Imeth treatment because dehydration (reduction of body water) can increase the toxicity of Imeth.

Pregnancy, lactation and fertility

If you are pregnant or breastfeeding, think you may be pregnant or intend to become pregnant, consult your doctorbefore using this medication.

Pregnancy

Do not use Imeth during pregnancy or if you are trying to become pregnant. Methotrexate can cause birth defects, damage the fetus or cause miscarriages. It is associated with skull, facial, heart and blood vessel malformations, brain and limb defects. 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, 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 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 adverse effects on 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.

Lactation

You should not breastfeed during treatment, as methotrexate passes into breast milk. If your doctor considers that methotrexate treatment is absolutely necessary during lactation, you should interrupt breastfeeding.

Male fertility

The available data do not indicate a higher risk of malformations or miscarriages if the father takes a dose of methotrexate less than 30 mg/week. However, this risk cannot be completely ruled out. Methotrexate may be genotoxic, meaning it can cause genetic mutations. Methotrexate may 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

During treatment with Imeth, you may experience adverse effects that affect the central nervous system, such as fatigue and dizziness. Therefore, in some cases, your ability to drive vehicles and/or operate machinery may be affected. If you feel tired or dizzy, you should not drive or operate machinery.

IMETH contains sodium

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

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

Imethis administeredonly once a week. You can decide, along with your doctor, a suitable day of the week for each week you receive your injection.

Incorrect administration of Imethmay cause severe adverse effects, including potentially fatal adverse effects.

The normal dose is:

Posology in patients with rheumatoid arthritis

The recommended initial dose is 7.5mg of methotrexateonce a week. Imethis administered in a single application in the form of an injection under the skin (see section "Method and duration of administration").

If this is inadequate and well tolerated, Imethdoses can be increased. The average weekly dose is 15-20mg. Generally, aweekly doseof 25mg of Imeth should not be exceeded. Once the desired therapeutic results are achieved, the dose should be reduced, if possible, gradually to the lowest possible maintenance dose.

Posology in children and adolescents under 16 years with polyarticular forms of juvenile idiopathic arthritis

The recommended dose is 10-15mg/m2of body surfaceper week. In cases of inadequate response, the weekly dose can be increased to 20mg/m2of body surface/week. However, more frequent medical checks should be performed. It should be administered via subcutaneous injection (under the skin).

It is not recommended to use in children under 3 years due to insufficient experience in this age group.

Adults with severe forms of psoriasis vulgar or psoriatic arthritis

It is recommended to administer a single test dose of 5-10mg to evaluate potential harmful effects. This dose can be administered subcutaneously (under the skin).

If no changes in blood counts are observed one week later, treatment should continue with a dose of approximately 7.5mg. The dose can be increased gradually (in amounts of 5-7.5mg per week and controlling blood counts) until the desired therapeutic results are achieved. Generally, aweekly doseof 20mg can be associated with a significant increase in toxicity. A weekly dose of 30mg should not be exceeded. Once the desired therapeutic results are achieved, the dose should be reduced weekly to the lowest possible maintenance dose for the patient.

Posology in adult patients with Crohn's disease

The duration of treatment will be determined by the doctor. Crohn's disease treatment with Imeth is a long-term treatment.

• Induction treatment:

25 mg/week administered subcutaneously.

Response to treatment can be expected approximately 8 to 12 weeks after starting treatment.

• Maintenance treatment:

15 mg/week administered subcutaneously.

This medication is not indicated for pediatric patients with Crohn's disease.

Patients with renal impairment

Patients with renal impairment may require a reduced dose.

Method and duration of administration

The doctor will determine the duration of treatment. Imethis injectedonce a week. It is recommended to specify a particular day of the week as the injection day. Imethis administered in the form of an injection under the skin. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgar, and psoriatic arthritis with Imethis a long-term treatment.

Rheumatoid arthritis

Generally, an improvement in symptoms can be expected within 4-8 weeks of treatment. Symptoms may recur after discontinuation of Imethtreatment.

Severe forms of psoriasis vulgar and psoriatic arthritis (psoriatic arthritis)

Response to treatment can be expected generally within 2-6 weeks. Depending on the clinical picture and changes in laboratory parameters, treatment will be continued or discontinued.

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

How to administer an IMETH injection

If you do not know how to handle the syringe, ask your doctor or pharmacist. Do not attempt to administer the injection yourself if you have not received training. If you are unsure of what to do, speak immediately with your doctor or nurse.

Before injecting IMETH

• Check the expiration date of the medication. Do not use it if the expiration date has passed.
• Check that the syringe is not damaged and that the medication has a clear appearance. If not, use another syringe.
• Inspect the last injection site to see if the last injection has caused any redness, skin color change, swelling, pus, or persistent pain; if so, speak with your doctor or nurse.
• Decide where you will inject the medication. Change the injection site each time you administer an injection.

Instructions on how to inject IMETH

1) Wash your hands thoroughly with water and soap.

2) Sit or lie down in a comfortable and relaxed position. Make sure you can see the area of skin where you will administer the injection.

3) The syringe is preloaded and ready to use. Open the blister pack, exposing the top layer of the blister pack completely as shown.

4) Caution: DO NOT hold the product by the plunger or the cap of the needle. Remove the syringe from the box by holding it by the body as shown in the image below.

5) Visually inspect the syringe. You should be able to see a yellow liquid through the viewing window. You may see a small air bubble; this will not affect the injection and will not cause any harm.

6) Choose an injection site and disinfect it with the alcohol-soaked swab provided. This takes 30 to 60 seconds to take effect. Suitable areas for injection are the skin of the front of the abdominal wall and the skin of the front of the thigh.

7) While holding the body of the syringe, remove the cap.

Do notpress the plunger before self-injecting to remove air bubbles. If you do, you may lose medication. After removing the cap, hold the syringe in your hand. Avoid letting the syringe come into contact with any other object. This ensures that the needle remains clean.

8) Hold the syringe with the hand you write with (as if holding a pen) and, with the other hand, form a fold in the skin by gently pinching the skin at the injection site with your index and middle fingers.Make sure to hold the skin fold throughout the injection.

9) Move the syringe towards the skin fold (injection site) with the needle guard pointing directly at the injection site. Insert the needle until it reaches the bottom of the skin fold.

10) Press the plunger down with your finger until the syringe is empty. This will inject the medication under the skin.

11) Remove the needle; to do this, pull it straight out. The safety guard of the syringe will automatically cover the needle to prevent needlestick injuries. You can now release the skin fold.

Nota: The safety system that releases the safety guard can only be activated when the syringe is empty by pressing the plunger to the end.To avoid hematomas, do not rub the injection site after injecting.

12) Dispose of the syringe in the puncture container provided. Close the container lid tightly and place it out of reach of children. In case of accidental contact of methotrexate with the skin or soft tissues, rinse the area with plenty of water.When the container is full, hand it over to your doctor or nurse to dispose of it. Do not throw it away.

If you use moreIMETHthan you should

Follow the administration instructions of your doctor. Do not change the dose on your own.

If you suspect that you (or someone else) has administered too much Imeth, contact your doctor or go to the nearest hospital immediately. They will decide on the necessary therapeutic measures based on the severity of the overdose.

A methotrexate overdose can cause severe toxic reactions. Symptoms of overdose may include unusual bleeding or bruising, weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or coffee ground-like vomit, and decreased urine production. See section 4.

Take the packaging with the medication with you if you visit your doctor or a hospital.

The antidote for overdose is folic acid.

If you forget to useIMETH

Do not take a double dose to make up for the missed dose, but continue taking the prescribed dose. Ask your doctor for advice.

If you interrupt treatment withIMETH

Do not interrupt or discontinue treatment with Imeth unless you have agreed to do so with your doctor. If you suspect severe adverse effects, contact your doctor immediately.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

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

Inform your doctor immediately if you experience sudden weakness; difficulty breathing; swelling of the eyelids, face, or lips; skin rash or itching (especially if it affects the entire body).

Severe side effects

If you develop any of the following severe side effects, contact your doctor immediately:

• Respiratory problems (symptoms may include general discomfort, irritating and dry cough, difficulty breathing, feeling of lack of air at rest, chest pain, or fever).
• Bleeding when coughing or sneezing.
• Formation of blisters or severe skin peeling.
• Unusual bleeding (including vomiting blood) or bruises.
• Severe diarrhea.
• Mouth ulcers.
• Black or tar-like stools.
• Blood in urine or stools.
• Small red spots on the skin.
• Fever.
• Yellow discoloration of the skin (jaundice).
• Pain or difficulty urinating.
• Thirst and/or frequent urination.
• Seizures (convulsions).
• Loss of consciousness.
• Blurred vision or decreased vision.

The following side effects have also been reported:

Very common:

Loss of appetite, nausea (dizziness), vomiting, abdominal pain, inflammation, and ulcers in the mouth and throat, and increased liver enzymes.

Common:

Reduced formation of blood cells with a decrease in white blood cells, red blood cells, and/or platelets (leukopenia, anemia, thrombocytopenia), headache, fatigue, drowsiness, lung inflammation (pneumonia) with dry, non-productive cough, difficulty breathing, and fever, diarrhea, skin rash, redness, and itching.

Uncommon:

Decreased number of blood cells and platelets, dizziness, confusion, depression, seizures, inflammation of blood vessels, lung damage, ulcers, and bleeding in the digestive tract, liver disorders, diabetes, decreased blood proteins, urticaria (hives), sunburn-like reactions due to increased skin sensitivity to sunlight, brown discoloration of the skin, hair loss, increased rheumatoid nodules, herpes, painful psoriasis, joint or muscle pain, osteoporosis (bone mass reduction), inflammation, and ulcers in the bladder (possibly with blood in the urine), painful urination, severe allergic reactions, inflammation, and ulcers in the vagina, and slow wound healing.

Rare:

Lung inflammation, fluid in the sac surrounding the heart, severe vision impairment, mood swings, low blood pressure, blood clots, sore throat, respiratory arrest, asthma, digestive tract inflammation, bloody stools, gum inflammation, abnormal digestion, acute hepatitis (liver inflammation), nail color changes, acne, red or purple spots due to bleeding from blood vessels, bone fractures, kidney insufficiency, decreased or absent urine, electrolyte imbalances, defective sperm formation, and menstrual irregularities.

Very rare:

Infections, severe bone marrow insufficiency, liver insufficiency, swollen glands, insomnia, pain, muscle weakness, numbness or tingling/sensitivity to minor stimuli, altered taste (metallic taste), inflammation of the brain's meninges causing paralysis or vomiting, red eyes, retinal damage, fluid in the lungs, vomiting blood, fever, protein in the urine, loss of libido, erectile dysfunction, nail infections, severe digestive tract complications, boils, small blood vessels in the skin, fungal infections, skin blood vessel damage, vaginal discharge, infertility, and gynecomastia (breast enlargement in men), lymphoproliferative disorders (excessive increase in white blood cells).

Unknown frequency:

Some brain infections (leucoencephalopathy), pulmonary hemorrhage, jawbone damage (secondary to excessive white blood cell increase), tissue destruction at the injection site, skin redness, and peeling, swelling.

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

Methotrexate may cause a decrease in white blood cells and reduce your resistance to infection. If you experience an infection with symptoms such as fever and severe deterioration of your overall health, or fever with local infection symptoms such as sore throat, pharyngitis, mouth pain, or urinary problems, seek immediate medical attention. A blood test will be performed to check for possible white blood cell reduction (agranulocytosis). It is essential to inform your doctor about your medication.

Methotrexate can cause severe side effects (sometimes life-threatening). Your doctor will perform tests to check for any abnormalities in your blood (e.g., low white blood cells, low platelets, lymphoma) and changes in your kidneys and liver.

Reporting side effects
Ifyou experience any type of side effect, consult your doctor or pharmacist, even if it is not listed in this prospectus. You can also report them directly through the national notification system included in the Spanish System for Pharmacovigilance of Medicinal Products for Human Use:www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

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

Store at a temperature below 25°C.

Store the syringe in the outer box to protect it from light.

Do not freeze.

Do not use this medication after the expiration date that appears on the pre-filled syringe label and the box after CAD. The expiration date is the last day of the month indicated.

The product must be used immediately after opening.

Do not use Imeth if the solution is not transparent and contains particles.

For single use. Dispose of any unused solution remainder. Medications should not be thrown away through drains or in the trash. Deposit containers and unused medications at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of containers and unused medications. By doing so, you will help protect the environment.

Composition of IMETH

• The active ingredient is methotrexate. 1ml of solution contains 25mg of methotrexate.

• The other components are sodium chloride, sodium hydroxide, and water for injection preparations.

Appearance of IMETH and packaging contents

Pre-filled syringes of Imeth contain a transparent and yellowish solution. Pre-filled syringes come equipped with a injection needle and a safety device to prevent needlestick injuries and reuse.

The following packaging sizes are available:

Pre-filled syringes of 0.3ml containing 7.5mg of methotrexate.

Pre-filled syringes of 0.4ml containing 10mg of methotrexate.

Pre-filled syringes of 0.5 ml containing 12.5 mg of methotrexate.

Pre-filled syringes of 0.6 ml containing 15 mg of methotrexate.

Pre-filled syringes of 0.7 ml containing 17.5 mg of methotrexate.

Pre-filled syringes of 0.8 ml containing 20 mg of methotrexate.

Pre-filled syringes of 0.9 ml containing 22.5 mg of methotrexate.

Pre-filled syringes of 1.0 ml containing 25 mg of methotrexate.

Injectable solution in packaging of 1, 4, 6, and 24 pre-filled syringes.

Each packaging of 1, 4, 6, and 24 pre-filled syringes contains 2, 8, 12, and 48 alcohol swabs, respectively.

Only some packaging sizes may be commercially available.

Marketing authorization holder and responsible manufacturer

Marketing authorization holder

Nordic Group B.V.

Siriusdreef 41

2132 WT Hoofddorp

Netherlands

For more information about this medicine, please contact the local representative of the marketing authorization holder:

Nordic Pharma SAU

Adolfo Pérez Esquivel 3, 2nd Floor 17.

28232 Las Rozas (Madrid)

Spain

Responsible manufacturer

Cenexi - Laboratoires Thissen SA

Rue de la Papyree 2-6, Braine-L'’Alleud, Brabant Wallon

B-1420

Belgium

This medicine is authorized in the European Economic Area member states with the following names:

France:

iMETH 12.5 mg/0.5 ml, solution injectable en seringue préremplie

Netherlands

Methotrexaat Nordic 12.5 mg Oplossing voor injectie in een voorgevulde spuit

United Kingdom

Zlatal 12.5 mg, solution for injection in pre-filled syringe

Last review date of this leaflet: August 2024

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