Patient Information Leaflet

Wyeth 2.5 mg Weekly Methotrexate Tablets

DO NOT EXCEED THE RECOMMENDED DOSE PRESCRIBED BY YOUR DOCTOR. THE DOSE FOR RHEUMATOID ARTHRITIS, JUVENILE IDIOPATHIC ARTHRITIS, PSORIASIS, PSORIATIC ARTHRITIS, REACTIVE ARTHRITIS, ACUTE LYMPHOBLASTIC LEUKEMIA AND LYMPHOMASIS ADMINISTERED ONCE A WEEK. CASES OF DEATH HAVE BEEN REPORTED RELATED TO DAILY ADMINISTRATION OF THIS MEDICAMENT INSTEAD OF WEEKLY. CONSULT YOUR DOCTOR OR PHARMACIST IF YOU ARE UNSURE ABOUT HOW MUCH AND HOW OFTEN YOU SHOULD TAKE THIS MEDICINE.

Read this leaflet carefully before you start taking 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, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it 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, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

Wyeth Weekly Methotrexate belongs to a group of medicines called folate acid analog antimetabolites.

Methotrexate in high doses is indicated for the treatment of some types of cancer such as leukemias and lymphomas.

Methotrexate in low doses is indicated for:

• The treatment of various types of arthritis, such as active and severe rheumatoid arthritis in adult patients, and polyarticular idiopathic juvenile arthritis, active and severe, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.
• The treatment of psoriasis and psoriatic arthritis when other treatments have failed.
• The treatment ofreactive arthritiswhen other treatments have failed.

Before starting to use this medication, you must consult your doctor about the risks and benefits of treatment with methotrexate. It is very important that you use methotrexate exactly as your doctor has instructed you.If you use methotrexate more frequently or in higher doses than indicated by your doctor, you may suffer from severe adverse reactions, including death.

Do not take MetotrexateweeklyWyeth

• If you are allergic to methotrexate or to any of the other components of this medication(including in section 6).
• If you have liver function abnormalities (liver insufficiency).
• If you have severe kidney function abnormalities (severe renal insufficiency).
• If you have liver damage due to excessive alcohol consumption (alcoholic hepatitis), if you have chronic liver damage (chronic hepatitis) or if you are an alcoholic.
• If you have altered blood levels of red blood cells, white blood cells, and platelets.
• If you have any immune system disease (immunodeficiency syndromes).
• Severe, acute, or chronic infections such as tuberculosis and HIV.
• If you have ulcers in the mouth, stomach, or intestines.
• If you are going to be vaccinated.

• If you are breastfeeding

Additionally, in non-oncological indications (treatment not related to cancer)

• Si are pregnant (see section «Pregnancy, breastfeeding, and fertility»);

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to take this medication.

• Take MetotrexateweeklyWyeth once a week.
• Daily intake of the medication by mistake produces severe and life-threatening toxicity.

Your doctor will inform you of the benefits and risks of treatment with methotrexate, as well as the symptoms that may indicate possible toxicity due to the medication.

If you find yourself in any of the following cases, consult your doctor before using this medication.

• If you develop signs or symptoms due to possible medication toxicity at the gastrointestinal and/or neuronal level, in the liver, kidneys, lungs, blood, or skin, go to your doctor.
• Follow the dose scrupulously as indicated by your doctor, for example, a prescribed weekly dose that is administered by mistake daily, may lead to toxicity, even fatal.
• It is not recommended to use this medication in the treatment of neoplastic diseases in women of childbearing age, unless there is clear medical evidence that the expected benefits outweigh the risks.
• If you have folate deficiency, as it may increase the toxicity of methotrexate.
• If you present vomiting, diarrhea, or inflammation of the mouth (stomatitis), inform your doctor, as you may become dehydrated. If this occurs, your doctor may interrupt your treatment until you recover completely. Also, inform your doctor if you have peptic ulcers or any type of colitis.
• If you have altered blood levels of white blood cells, red blood cells, and platelets. Methotrexate may decrease white blood cells in the blood. If this occurs, you should take a series of precautions that include: avoiding contact with people with infections; consulting your doctor if you think you may have an infection due to the presence of fever or chills, cough, back pain, or difficulty urinating; consult your doctor before undergoing dental procedures. Additionally, methotrexate may decrease the number of platelets in the blood necessary for coagulation. Therefore, it is essential to consult your doctor in the presence of noticeable petechiae or bleeding from the gums or nose, red spots on the skin, blood in the urine or black stools, and communicate with your dentist that you are being treated with methotrexate.
• If you are being treated with NSAIDs (nonsteroidal anti-inflammatory drugs).
• If you have liver problems, as methotrexate may cause acute hepatitis and chronic liver disorders. Moderate liver abnormalities may require closer monitoring by your doctor but do not lead to the suspension of treatment. Alcohol, obesity, advanced age, or the use of products containing arsenic may increase the risk of liver problems.
• If you have kidney problems, as methotrexate may cause renal damage.
• If you have any type of infection.
• If you are going to be vaccinated, as it may cause severe infection or the response to the vaccine may decrease.
• If during or after treatment you experience symptoms of toxicity at the nervous system level, such as headache, back pain, stiffness in the neck, fever, confusion, irritability, drowsiness, discoordination in movements, dementia, convulsions, transient blindness, abnormal reflexes, localized abnormalities of movement and perception.
• If during treatment you experience dry cough, fever, chest pain, and/or difficulty breathing, inform your doctor.
• If during treatment or days after you develop skin alterations, consult your doctor. Skin lesions in patients with psoriasis may worsen with exposure to sunlight. Previous skin lesions and sunburns may reappear with the use of methotrexate. Methotrexate may make the 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-factor sunscreen.
• A severe pulmonary hemorrhage has been reported with methotrexate in patients with underlying rheumatological disease. If you observe blood when coughing or spitting, you should immediately contact your doctor.
• Methotrexate temporarily affects the production of sperm and eggs. Methotrexate may cause abortions and severe birth defects. If you are a woman, you should avoid pregnancy during treatment with methotrexate and for at least 6 months after completing treatment with methotrexate. If you are a man, you should avoid fathering a child if you are being administered methotrexate at the time and for at least 3 months after completing treatment. See also section «Pregnancy, breastfeeding, and fertility».
• 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 central nervous system infection called progressive multifocal leukoencephalopathy (PML).

Recommended precautions and complementary analyses

Even if methotrexate is used at low doses, severe adverse effects may occur. To detect them in time, your doctor should perform control analyses and laboratory tests.

Before starting treatment:

Before starting treatment, your blood will be analyzed to see if you have enough blood cells. Your blood will also be analyzed to check liver function and to see if you have hepatitis. In addition, your blood will be checked for serum albumin (a protein in the blood), liver status (hepatic infection), and renal 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 for closer examination. Your doctor may also check if you have tuberculosis and take a chest X-ray or perform a respiratory function test.

During treatment:

Your doctor may perform the following controls:

- Examine the oral cavity and pharynx to detect changes in the mucosa, such as inflammation or ulceration;

- Blood analysis/hemogram with blood cell count and measurement of serum methotrexate levels;

- Blood analysis to control liver function;

- Diagnostic imaging tests to control liver status;

- Small sample of liver tissue extracted for closer examination;

- Blood analysis to control renal function;

- Control of respiratory pathways, and if necessary, respiratory function test.

It is very important that you attend these scheduled controls.

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

Patients of advanced age

Patients of advanced age being treated with methotrexate should be closely monitored by a doctor to detect possible adverse effects as soon as possible.

The deterioration of liver and renal function related to age, as well as the low vitamin B12 reserves in the elderly, require a relatively low dose of methotrexate.

Your doctor will regularly monitor your condition to check if the medication is having the expected effect.

Children, adolescents, and elderly people

Children, adolescents, and elderly people being treated with methotrexate should be closely monitored by a doctor to detect possible adverse effects as soon as possible.

It is not recommended to use this medication in children under 3 years of age because the experience with the use of this medication is insufficient in that age group

Other medicationsand MetotrexateweeklyWyeth

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

It is especially important to inform your doctor if you are taking any of the following medications:

• Medications used to treat certain types of cancer, such as cisplatin, mercaptopurine, cytarabine, and L-asparaginase.
• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and other salicylates, and especially ketoprofen.
• Inhibitors of the proton pump (used to treat stomach ulcers).
• Leflunomide (medication for rheumatoid arthritis).
• Metamizol (synonyms novaminsulfon and dipirona) (medication for intense pain and/or fever).
• Medications with high plasma protein binding (such as salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylureas, amino benzoic acid, some antibiotics, and medications for abnormal cholesterol and lipid levels such as cholestyramine).
• Probenecid (medication used to reduce uric acid levels).
• Antibiotics (ciprofloxacin, penicillins, sulfonamides, tetracyclines, chloramphenicol, pyrimethamine, trimethoprim/sulfamethoxazole) and broad-spectrum antibiotics that are not absorbed in the digestive tract.
• Medications that cause liver toxicity (such as leflunomide, azathioprine, sulfasalazine, and retinoids).
• Theophylline (medication for asthma).
• Vitamins or vitamin preparations containing folic acid or its derivatives.
• Nitrous oxide (anesthetic).
• Amiodarone (medication for cardiac arrhythmias).
• Diuretics (such as triamterene).

Additionally, certain therapies may interact with methotrexate. This is the case of PUVA therapy (methoxsalen and ultraviolet light) in patients with psoriasis or a disease called mycosis fungoides, as well as radiation therapy.

During treatment with methotrexate, you should exercise caution when receiving a blood transfusion.

Use of MetotrexateweeklyWyeth with food, drinks, and alcohol

While taking methotrexate, you should avoid consuming alcohol, as this may increase the likelihood of adverse effects, especially in the liver.Avoid excessive consumption of coffee, fizzy drinks containing caffeine, and black teaYour doctor may instruct you to take more liquids than usual. This will help you eliminate the medication and prevent kidney problems.

Pregnancy, breastfeeding, and fertility

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

Consult your doctor or pharmacist before using any medication.

• Pregnancy:

Do not use this medication during pregnancy except if your doctor has prescribed it as oncological treatment (cancer treatment). Methotrexate may cause birth defects, harm the fetus, or cause abortions. It is associated with cranial, facial, heart, and vascular malformations, brain, and limb defects. Therefore, it is very important that it is not administered to pregnant women or women who plan to become pregnant, unless it is used as oncological treatment.

In non-oncological indications (not related to cancer) in women of childbearing age, any possibility of pregnancy should be excluded, for example, by a pregnancy test, before starting treatment.

Do not use this medication if you are trying to become pregnant. You should avoid becoming pregnant while taking methotrexate and for at least 6 months after completing treatment. To do this, you should ensure that you are using reliable contraceptive methods during that time (see also section «Warnings and precautions»).

If you become pregnant during treatment or suspect that you may be pregnant, consult your doctor as soon as possible. If you become pregnant during treatment, you should receive information about the risk of harmful 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 starting treatment.

• Breastfeeding:

Do not breastfeed your child during treatment, as methotrexate passes into breast milk. If your doctor considers it absolutely necessary to continue treatment with methotrexate during the breastfeeding period, you should stop breastfeeding.

• Male fertility:

The available data do not indicate a higher risk of malformations or abortions if the father takes a methotrexate dose of less than 30 mg/week. However, this risk cannot be completely ruled out, and there is no information on higher doses of methotrexate. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm production, which is associated with the possibility of birth defects.

Therefore, you should avoid fathering a child or donating semen during treatment with methotrexate and for at least 3 months after completing treatment. Since treatment with methotrexate at higher doses commonly used in cancer treatment may cause infertility and genetic mutations, men treated with methotrexate doses higher than 30 mg/week should consider semen conservation before starting treatment (see also section «Warnings and precautions»).

Driving and operating machinery

Do not drive vehicles or operate machinery after taking Metotrexate weekly Wyeth, as some of the possible adverse effects, such as dizziness and fatigue, may affect your ability to drive vehicles and operate machinery.

MethotrexateweeklyWyeth contains lactose

This medication contains lactose. If your doctor has told you that you are intolerant to certain sugars, consult with them before taking this medication.

Follow exactly the administration instructions of this medication indicated by your doctor or pharmacist and take only the number of tablets that your doctor has prescribed to treat your disease. In case of doubt, consult your doctor or pharmacist again.If you use methotrexate more frequently or in higher doses than indicated by your doctor, you may experience severe adverse reactions, including death.

Recommended dose:

Dose in rheumatoid arthritis, psoriasis and reactive arthritis:

Take Methotrexate weekly Wyeth 2.5 mg tabletsonly once a week.

The initial dose for rheumatoid arthritis in adults is 3 tablets (7.5 mg)once a week. According to the evolution of treatment, your doctor may consider increasing the dose by 1 tablet every 6-8 weeks, up to a maximum dose of 8 tablets (20 mg)per week.

The recommended initial dose for juvenile idiopathic polyarticular arthritis is 10-15 mg/m2once a weekadministered orally.

The initial dose in adults forpsoriasis and psoriatic arthritisis 3 tablets (7.5 mg)once a week.According to the evolution of treatment, your doctor may consider increasing the dose by 1 tablet every 4-6 weeks, up to a maximum dose of 10 tablets (25 mg)per week.

The recommended dose forreactive arthritisis 3 tablets (7.5 mg)once a week.According to the evolution of treatment, your doctor may consider increasing the dose up to a maximum dose of 8 tablets (20 mg)per week.

Dose in leukemias and lymphomas:

Your doctor will indicate what dose you should take for your disease and when you should take it. Take exactly that dose.

It may take several months before you can appreciate the complete benefits of this medication. Do not increase your dose or take this medication more frequently or for a longer period than prescribed. Your disease will not improve faster and instead you may increase your risk of experiencing adverse effects, which could be potentially fatal.

Graphic information on taking tablets in inflammatory indications for adults

Each package of Methotrexate weekly Wyeth contains 24 tablets, which are presented divided into 2 blisters, each containing 12 tablets. Each tablet contains a dose of 2.5 mg of methotrexate. Below are graphic schemes of the recommended number of tablets to take for each of theinflammatory indicationsdescribed above. It is very important that you follow your doctor's instructions and take only the correct number of tablets that your doctor has prescribed for your disease. Remember also that taking the tablets indicated by your doctor should be done 1 time per week.Please notethe day chosen for weekly intake in the space provided for this purpose in the package.

RA, PSORIASIS AND PSORIATIC ARTHRITIS

Theinitial dose in adults is 3 tablets (7.5 mg)once a week. Therefore, thepackage of Methotrexate weekly Wyeth containing 24 tabletscovers the treatment for 8 weeks, distributing the tablets as follows:

If the dose had to be increased, 1 additional tablet (2.5 mg) would be added per week, i.e. 4 tablets per week. In this case, thepackage of Methotrexate weekly Wyeth with 24 tabletswould cover the treatment for 6 weeks, as follows.

REACTIVE ARTHRITIS

Therecommended dose is 3 tablets (7.5 mg) to 8 tablets (20 mg)once a week. Therefore, thepackage of Methotrexate weekly Wyeth containing 24 tabletscovers the treatment for 8 weeks at the initial dose of 3 tablets (7.5 mg), distributing the tablets as follows:

If your doctor increased the dose, he would add 1 additional tablet (2.5 mg) per week up to a maximum of 8 tablets (20 mg) per week. Only in the case where your doctor prescribes the maximum dose, thepackage of Methotrexate weekly Wyeth with 24 tabletswould cover the treatment for 3 weeks, as follows.

Use in elderly patients

Elderly patients should receive a relatively low dose due to the decrease in liver and kidney function and the lower folate reserves related to age.

Use in patients with kidney and liver problems

Consult your doctor as it may be necessary to adjust the dose and in some cases the medication may be contraindicated.

Use in children

Your doctor will calculate the necessary dose based on the child's body surface (m2), and the dose is expressed in mg/m2.

If you take more MethotrexateweeklyWyeth than you should

If you have taken more MethotrexateweeklyWyeth than you should, consult your doctor or pharmacist immediately.

In case of overdoseor accidental ingestion, consult the Toxicology Information Service, phone 91 562 04 20, indicating the medication and the amount ingested.

A methotrexate overdose can cause severe toxic reactions. The symptoms ofoverdose may include rapid formation of hematomas or hemorrhages, unusual weakness, mouth sores, nausea, vomiting, black stools or stools with blood, coughing up blood or vomiting with a coffee ground appearance and decreased urination (evacuation of urine from the bladder). See also section 4.

If you received more methotrexate than you should, it is recommended to administer folinic acid as soon as possible, as well as hydrate and alkalize the urine.

If you forgot to takeMethotrexateweeklyWyeth

Do not take a double dose to compensate for the missed doses. Take the next dose when it is due.

If you interrupt treatment withMethotrexateweeklyWyeth

Do not interrupt treatment unless your doctor tells you to. If you have any other questions about the use of this medication, ask your doctor, pharmacist or nurse.

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.

If you consider that any of the side effects you are experiencing are severe or if you notice any side effect not mentioned in this leaflet, inform your doctor or pharmacist.

Inform your doctor immediatelyif you experience ringing in the ears, difficulty breathing, swelling of the eyelids, face, or lips, skin rash, or itching (especially if it affects your entire body).

Inform your doctor immediately if you notice any of the following side effects:

• breathing problems (symptoms may include general feeling of discomfort, dry and irritating cough, shortness of breath, difficulty breathing, chest pain, or fever)
• blood when coughing or spitting*
• severe peeling or blisters on the skin
• bleeding (including blood in vomit) or unusual bruising or nasal bleeding
• nausea, vomiting, abdominal discomfort, or intense diarrhea
• mouth sores
• black or tar-like stools
• blood in urine or stools
• red spots on the skin
• fever, sore throat, flu-like symptoms
• yellow discoloration of the skin (jaundice) or dark-colored urine
• pain or difficulty urinating
• thirst and/or frequent urination
• seizures (convulsions)
• loss of consciousness
• restricted or blurred vision
• intense fatigue

*reported with methotrexate when used in patients with underlying rheumatological disease.

The following side effects have also been reported:

Very common(may affect more than 1 in 10 people):

• loss of appetite, nausea (urge to vomit), vomiting, abdominal pain, digestive problems, inflammation, and ulcers in the mouth and throat
• blood tests indicating an increase in liver enzymes.

Common(may affect up to 1 in 10 people):

• infections
• reduced formation of red blood cells, white blood cells, or platelets (leucopenia, anemia, thrombocytopenia)
• headache, fatigue, dizziness
• inflammation of the lungs (pneumonia) with dry cough, difficulty breathing, and fever
• diarrhea
• skin rash, redness of the skin, and itching.

Rare(may affect up to 1 in 100 people):

• lymphoma (swelling in the neck, groin, or armpits, accompanied by back pain, weight loss, or night sweats)
• severe allergic reactions
• diabetes
• depression
• dizziness, confusion, seizures
• lung damage
• ulcers and bleeding in the digestive tract
• liver disease, decreased blood proteins
• urticaria, sunburn-like reactions due to increased skin sensitivity to sunlight
• brown discoloration of the skin, hair loss, increased number of rheumatoid nodules, herpes zoster, painful psoriasis, slow wound healing
• joint or muscle pain, osteoporosis (bone softening)
• kidney disease, inflammation, or ulcers of the bladder (possibly with blood in the urine), painful urination
• inflammation and ulcers in the vagina.

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

• systemic viral, fungal, or bacterial infections
• severe bone marrow disorder (anemia)
• lymphoproliferative disorders (excessive growth of white blood cells)
• insomnia
• pain, muscle weakness, changes in taste (metallic taste), inflammation of the membrane covering the brain with paralysis or vomiting, numbness or tingling/sensitivity to minor stimuli
• speech muscle movement disorder, difficulty speaking, language impairment, feeling of sleepiness or fatigue, feeling of confusion, abnormal sensations in the head, inflammation of the brain, ringing in the ears
• redness of the eyes, eye damage
• fluid accumulation in the lungs, pulmonary infections
• vomiting with blood, severe complications in the digestive tract
• liver insufficiency
• finger or toenail infections, nail separation from the nail bed, boils, dilation of small blood vessels, skin damage, allergic inflammation of blood vessels
• protein in the urine
• decreased libido, erectile dysfunction, vaginal discharge, infertility, breast enlargement in men (gynecomastia)
• fever.

Frequency not known(cannot be estimated from available data):

• pathological changes in the white matter of the brain (leucoencephalopathy)
• hemorrhages
• lung hemorrhage*
• redness and peeling of the skin
• jawbone fractures (secondary to excessive white blood cell formation)
• swelling

*reported with methotrexate when used in patients with underlying rheumatological disease.

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect not listed in this leaflet. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use:https://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.

Do not store at a temperature above 25°C.

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

Medications should not be disposed of through drains or in the trash.Deposit the packaging and medications you no longer need atthe SIGREpoint at the pharmacy. If in doubtask your pharmacist how to dispose of the packaging and medications you no longer need. By doing so, you will help protect the environment.

Metotrexate CompositionWeeklyWyeth

• The active ingredient is metotrexate.
• The other components are: cornstarch, lactose monohydrate, magnesium stearate and sodium hydroxide.

Appearance of the product and contents of the packaging

MetotrexateWeeklyWyeth 2.5 mg tablets are presented in PVC/aluminum blisters containing 24 tablets for oral administration.

Marketing Authorization Holder

WYETH FARMA, S.A.

Ctra. Burgos, Km. 23

San Sebastián de los Reyes

28700 – Madrid

Spain

Responsible for Manufacturing

Excella GmbH & Co. KG

NürnbergerStrasse 12,

90537 Feucht,

Germany

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

Pfizer, S.L.

Avda. de Europa, 20-B

Parque Empresarial La Moraleja

28108 Alcobendas (Madrid)

Spain

Last review date of this leaflet:March 2025.

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