METOTREXATE WYETH 25 mg/mL Injectable Solution

Introduction

Package Leaflet: Information for the User

Methotrexate Wyeth 25 mg/ml Solution for Injection

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.Keep this leaflet. You may need to read it again.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What Methotrexate Wyeth is and what it is used for

Methotrexate belongs to a group of medicines called folate analogues.

Methotrexate is used at high doses to treat many types of cancer. At lower doses, it can also be used to treat psoriasis and rheumatoid arthritis.

Methotrexate is indicated for the treatment of various tumor diseases such as gestational trophoblastic neoplasia (development of a tumor directly associated with pregnancy), acute leukemia, breast cancer, head and neck cancer, bladder cancer, osteosarcoma (bone cancer), and malignant lymphomas. It is also indicated for the prevention and treatment of meningeal leukemia (leukemic infiltration of the central nervous system).

In addition, it is used in the treatment of severe rheumatoid arthritis; in the treatment of juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis (only when the severity requires it and other treatments have failed).

It is also indicated as prophylaxis for graft-versus-host disease in allogeneic bone marrow transplantation.

2. What you need to know before you use Methotrexate Wyeth

Before you start using this medicine, you should consult your doctor about the risks and benefits of using methotrexate. It is very important that you use methotrexate exactly as your doctor has recommended. If you use methotrexate more frequently or in higher doses than prescribed, you may suffer from serious illnesses, including death.

Do not use Methotrexate Wyeth:

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

In addition, in the case of non-oncological indications (not related to cancer)

• If you are pregnant (see section "Pregnancy, breastfeeding, and fertility");

Warnings and precautions:

Consult your doctor, pharmacist, or nurse before starting to use Methotrexate Wyeth.

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 medicine.

If you are in any of the following cases, consult your doctor before using this medicine.

• If you develop signs or symptoms due to possible toxicity of the medicine at the gastrointestinal and/or neuronal level, in the liver, kidney, lung, blood, or skin, consult your doctor.
• If you do not strictly follow the prescribed dose, for example, a weekly prescribed dose that is administered daily by mistake, it may lead to toxicity, even fatal.
• It is not recommended for use in the treatment of neoplastic diseases in women (cancer) of childbearing age, unless there is clear medical evidence that the expected benefits outweigh the risks.
• If you have folate deficiency, as it could increase the toxicity to methotrexate.
• If you present with vomiting, diarrhea, or inflammation of the mouth (stomatitis), inform your doctor, as you may become dehydrated. If this occurs, your doctor may interrupt treatment until you fully recover. Also, inform your doctor if you have peptic ulcer or any type of colitis.
• If you have alterations in blood levels of white blood cells, red blood cells, and platelets. Methotrexate can decrease the 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; consulting your doctor before undergoing dental interventions. Also, methotrexate can decrease the number of platelets in the blood necessary for coagulation. Therefore, it is essential that you consult your doctor in the presence of noticeable bruising or bleeding from the gums or nose, small red spots on the skin, blood in the urine or stools, and that you inform your dentist that you are being treated with methotrexate.
• If you are taking NSAIDs (non-steroidal anti-inflammatory drugs).
• If you have liver problems, as methotrexate can cause acute hepatitis and chronic liver disorders. Moderate liver alterations may appear that require closer monitoring by the doctor but do not lead to the suspension of treatment. Alcohol, obesity, advanced age, use of products containing arsenic can increase the risk of liver problems.
• If you have kidney problems, as methotrexate can cause kidney damage.
• If you suffer from any infectious process of any kind.
• If you are going to be vaccinated, as a severe infection may occur or the response to the vaccine may decrease.
• If during or after treatment, symptoms of toxicity at the level of the nervous system appear, such as headache, back pain, stiffness in the neck, fever, confusion, irritability, drowsiness, discoordination in movements, dementia, convulsions, transient blindness, abnormal reflexes, abnormal behavior, and localized alterations of movement and perception.
• If during treatment, you have a dry cough, fever, chest pain, and/or difficulty breathing, inform your doctor.
• If during treatment, you develop skin alterations, consult your doctor. Skin lesions in patients with psoriasis can worsen due to sun exposure. Previous skin lesions and sunburns before treatment may reappear with the use of methotrexate. Methotrexate can make the skin more sensitive to sunlight. Avoid intense sun exposure and do not use sunbeds or UV lamps without medical advice. To protect your skin from intense sun exposure, wear suitable clothing or use a sunscreen with a high protection factor.
• Methotrexate has been reported to cause acute pulmonary hemorrhage in patients with underlying rheumatological disease. If you observe blood when coughing or spitting, you should contact your doctor immediately.
• Methotrexate temporarily affects the production of sperm and eggs. Methotrexate can cause abortions and severe birth defects. If you are a woman, you should avoid becoming pregnant during treatment with methotrexate and for at least 6 months after the end of treatment with methotrexate. If you are a man, you should avoid fathering a child if you are being administered methotrexate at that time and for at least 3 months after the end of your treatment. See also section "Pregnancy, breastfeeding, and fertility".
• If you, your partner, or your caregiver notice the appearance or worsening of neurological symptoms, such as general muscle weakness, vision alterations, changes in thought, memory, and orientation that generate confusion and changes in personality, contact your doctor immediately because these can be symptoms of a rare and severe brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended precautions and complementary tests

Even if methotrexate is used at low doses, serious side effects may appear. To detect them in time, your doctor should perform control tests and analytical 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 the functioning of your liver and to see if you have hepatitis. Additionally, serum albumin (a protein in the blood), hepatitis status (liver infection), and renal function will be checked. The doctor may also decide to perform other liver tests, some of which may involve images of your liver and others that may require a small tissue sample from your liver to examine it more closely. 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 tests:

• examine the oral cavity and pharynx to detect changes in the mucosa, such as inflammation or ulceration;
• blood tests/hematogram with blood cell count and measurement of serum methotrexate levels;
• blood tests to monitor liver function;
• diagnostic imaging tests to monitor liver status;
• small tissue sample taken from the liver to examine it more closely;
• blood tests to monitor kidney function;
• control of the respiratory tract and, if necessary, pulmonary function test.

It is very important that you attend these scheduled tests.

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

Elderly patients

Elderly patients treated with methotrexate should be closely monitored by a doctor so that possible side effects can be detected as soon as possible.

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

Other medicines and Methotrexate Wyeth

Tell your doctor or pharmacist if you are using or have recently used or might use any other medicines.

Certain medicines may interact with methotrexate:

• Medicines used to treat some types of cancer, such as cisplatin, mercaptopurine, cytarabine, and L-asparaginase.
• Non-steroidal anti-inflammatory drugs, such as aspirin and other salicylates, and especially ketoprofen.
• Proton pump inhibitors (used to treat ulcers of the digestive system).
• Leflunomide (medicine for the treatment of arthritis).
• Metamizole (synonyms novaminsulfon and dipyrone) (medicine for intense pain and/or fever).
• Medicines with high binding to plasma proteins (such as salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonureas, aminobenzoic acid, some antibiotics, and medicines for the treatment of abnormal cholesterol and lipid levels such as colestyramine).
• Probenecid (medicine used to decrease uric acid levels).
• Antibiotics (ciprofloxacin, penicillins, sulfonamides, tetracyclines, chloramphenicol, pyrimethamine, trimethoprim/sulfamethoxazole) and broad-spectrum antibiotics that are not absorbed at the digestive level.
• Medicines that produce liver toxicity (such as leflunomide, azathioprine, sulfasalazine, and retinoids).
• Theophylline (medicine for the treatment of asthma).
• Vitamins or vitamin preparations that contain folic acid or its derivatives.
• Nitrous oxide (anesthetic).
• Amiodarone (medicine for the treatment of cardiac disorders).
• Diuretics (such as triamterene).

It is not recommended to administer certain types of vaccines during treatment with methotrexate.

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 radiotherapy.

During treatment with methotrexate, caution should be exercised when receiving a red blood cell transfusion.

Use of Methotrexate with food, drinks, and alcohol

While you are using methotrexate, you should avoid consuming alcohol, as this could increase the likelihood of side effects, especially in the liver. Your doctor may indicate that you drink more liquids than usual. This will help you eliminate the medicine and prevent kidney problems.

Pregnancy, breastfeeding, and fertility

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

Consult your doctor or pharmacist before using any medicine.

• Pregnancy:

Do not use this medicine during pregnancy except if your doctor has prescribed it as oncological treatment (treatment for cancer). Methotrexate can cause birth defects, harm the fetus, or cause abortions. It is associated with malformations of the skull, face, heart, and blood vessels, brain, and limbs. Therefore, it is very important that it is not administered to pregnant women or those 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 before starting treatment, for example, through a pregnancy test.

Do not use this medicine if you are trying to become pregnant. You should avoid becoming pregnant while taking methotrexate and for at least 6 months after the end of treatment. To do this, you should ensure that you are using reliable contraceptive methods during this entire 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 wish to become pregnant, consult your doctor, who may refer you to a specialist to inform you before the planned start of treatment.

• Male fertility:

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

For this reason, you should avoid fathering a child or donating semen during treatment with methotrexate and for at least 3 months after the end of treatment. Since treatment with methotrexate at higher doses commonly used in cancer treatment can cause infertility and genetic mutations, it is recommended that men treated with methotrexate doses higher than 30 mg/week consider sperm preservation before starting treatment (see also section "Warnings and precautions").

• Breastfeeding

Methotrexate has been detected in breast milk, so it is contraindicated during breastfeeding.

Driving and using machines:

It is not recommended to drive vehicles or use machines after the administration of Methotrexate Wyeth, as some of the possible side effects, such as dizziness and fatigue, may affect the ability to drive vehicles and use machines.

Methotrexate Wyeth contains sodium

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

3. How to use Metotrexato Wyeth

Methotrexate should only be prescribed by doctors with experience in the use of methotrexate and with a thorough knowledge of the risks of methotrexate treatment.

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

Your doctor will determine the dose and duration of treatment, as well as the most suitable administration route for you, according to your condition and response to treatment.

When you are given high doses of methotrexate, your doctor may prescribe you to take a vitamin called folic acid on subsequent days to prevent adverse effects of the medication. It is very important that you take the doses of folic acid as indicated by your doctor. Also, your doctor may insist that you drink plenty of fluids to prevent possible kidney problems.

If you use more Metotrexato Wyeth than you should

Although it is unlikely, if you receive more methotrexate than you should, it is recommended to administer folic acid as soon as possible, as well as hydration and alkalization of the urine. Additionally, you may experience some of the known adverse effects of the medication.

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

4. Possible side effects

Like all medications, this medication can cause side effects, although not all people suffer from them.

If you consider that any of the side effects you suffer from is serious or if you notice any side effect not mentioned in this prospectus, inform your doctor or pharmacist.

Tell your doctor immediatelyif you experience wheezing when breathing, difficulty breathing, swelling of the eyelids, face, or lips, skin rash, or itching (especially if it affects your whole body).

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

• breathing problems (symptoms may be 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 nosebleeds
• nausea, vomiting, abdominal discomfort, or severe diarrhea
• sores in the mouth
• black or tarry stools
• blood in urine or stools
• red spots on the skin
• fever, sore throat, flu-like symptoms
• yellowing of the skin (jaundice) or darkening of the urine
• pain or difficulty urinating
• thirst and/or frequent need to urinate
• seizures (convulsions)
• loss of consciousness
• restricted vision or blurred vision
• extreme fatigue

*has been 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, 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 (leukopenia, anemia, thrombocytopenia)
• headache, fatigue, dizziness
• inflammation of the lungs (pneumonia) with dry cough, difficulty breathing, and fever
• diarrhea
• skin rash, redness, and itching.

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

• lymphoma (lump 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, decrease in blood proteins
• hives, reactions similar to sunburn due to increased skin sensitivity to sunlight
• brown skin discoloration, hair loss, increased number of rheumatoid nodules, shingles, painful psoriasis, slow wound healing
• joint or muscle pain, osteoporosis (decrease in bone hardness)
• kidney disease, inflammation, or ulcers of the bladder (possibly with blood in the urine), pain when urinating
• inflammation and ulcers in the vagina.

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

• blood disorder characterized by the presence of very large red blood cells (megaloblastic anemia)
• mood changes
• weakness in movements, sometimes limited to the right or left side of the body
• significant visual disturbances
• inflammation of the sac surrounding the heart, accumulation of fluid in the sac surrounding the heart
• low blood pressure, blood clots
• tonsillitis, respiratory arrest, asthma
• inflammation of the pancreas, inflammation of the digestive tract, blood in the stool, inflammation of the gums, digestive problems
• acute hepatitis (liver inflammation)
• change in nail color, acne, red or purple spots due to bleeding in blood vessels
• worsening of psoriasis during treatment with UV radiation
• skin lesions similar to sunburn or radiation-induced dermatitis
• bone fractures
• kidney failure, decreased or absent urine production, abnormal electrolyte levels in the blood
• defective sperm formation, menstrual disorders.

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

• systemic viral, fungal, or bacterial infections
• severe bone marrow disorder (anemia), inflammation of the glands
• 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 stimuli less than normal
• alteration of muscle movement used for speech, difficulty speaking, language impairment, feeling of sleepiness or fatigue, feeling of confusion, abnormal sensations in the head, brain inflammation, ringing in the ears
• redness of the eyes, damage to the retina of the eye
• fluid accumulation in the lungs, lung infections
• vomiting blood, severe complications in the digestive tract
• liver failure
• nail infections, nail detachment from the nail bed, boils, dilation of small blood vessels, damage to blood vessels in the skin, allergic inflammation of blood vessels
• protein in the urine
• decreased libido, erection problems, vaginal discharge, infertility, breast enlargement in men (gynecomastia)
• fever.

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

• pathological changes in the white matter of the brain (leukoencephalopathy)
• bleeding
• pulmonary bleeding
• redness and peeling of the skin
• damage to the bones of the jaw (secondary to excessive growth of white blood cells)
• swelling, reaction at the injection site, tissue destruction at the injection site (necrosis at the injection site).

*has been 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 prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

5. Conservation of Metotrexato

Keep this medication out of sight and reach of children.

Store below 25°C.

Keep the vial in the outer packaging to protect it from light.

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

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This will help protect the environment.

6. Package contents and additional information

Composition of Metotrexato Wyeth

• The active ingredient is methotrexate.
• The other components are: sodium chloride and water for injectable preparations.

Appearance of the product and package contents

Metotrexato Wyeth 25 mg/ml injectable solution is presented in glass vials containing 40 ml of solution for intravenous, intramuscular, or intrathecal administration.

Each ml of solution contains 25 mg of methotrexate.

Each package contains 1 vial.

Marketing authorization holder and manufacturer:

Marketing authorization holder

WYETH FARMA, S.A.

Ctra. Burgos, Km. 23

San Sebastián de los Reyes

28700 – Madrid

Spain

Manufacturer:

Haupt Pharma Wolfratshausen GmbH

Pfaffenrieder Strasse. 5,

82515 Wolfratshausen,

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

Date of the last revision of this prospectus: March 2025.

Other sources of information

Detailed information about this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is intended only for healthcare professionals:

The use of Metotrexato Wyeth should be restricted to specialized services in the administration of chemotherapy and should only be administered under the supervision of a doctor specialized in the use of antineoplastic chemotherapy.

Method of administration

If Metotrexato Wyeth 25 mg/ml injectable solution needs to be diluted, it can be done in sodium chloride 0.9%, dextrose 5%, dextrose 10%, Ringer's lactate, or Ringer's solution.

Metotrexato Wyeth can be administered intravenously, intramuscularly, and intrathecally.

For intrathecal administration, methotrexate should be diluted without preservatives to a concentration of 1 mg/ml in a suitable sterile medium, without preservatives, such as sodium chloride 0.9% for injectables.

Methotrexate should not be mixed with other medications in the same drip bottle when administered intravenously. Especially, it should not be mixed with ranitidine, droperidol, or metoclopramide, as precipitation occurs. It has also been reported that methotrexate is incompatible with fluorouracil and prednisolone.

Metotrexato Wyeth does not contain any preservative agent. The vials are for single use, and the unused portion should be discarded after use.

When methotrexate is used in high doses or for intrathecal administration, the use of formulations or solvents containing preservatives is contraindicated.

As with other cytotoxic drugs:

• The preparation of methotrexate should be performed by trained healthcare personnel.
• Pregnant women should not handle methotrexate.
• The preparation should be carried out in a designated area (preferably in a cytotoxic laminar flow cabinet). The work surface should be protected with absorbent, plasticized, and disposable paper.
• When handling methotrexate, protective clothing should be used: protective glasses, gown, gloves, and disposable masks.
• If the solution accidentally comes into contact with the skin or mucous membranes, the affected area should be washed immediately with water or a sodium bicarbonate solution. Medical attention should be sought.
• Luer-Lock syringes are recommended. Large-diameter needles are also recommended to minimize pressure and possible aerosol formation. Aerosols can also be reduced by using a vented needle during preparation.
• Utensils used to dilute methotrexate or bodily waste items should be placed in a polyethylene bag and incinerated at 1100°C.

Disposal procedure

If spills occur, access to the affected area should be restricted. The use of rubber gloves, mask, protective gown, and safety glasses is recommended. Limit the spread of the spill by covering it with absorbent material, such as paper, etc. Spills can be treated with 5% sodium hypochlorite. Collect all absorbent material or other material used in the removal of the spill, put it in a plastic bag, and label it correctly. Cytotoxic waste should be clearly labeled with the legend "Cytotoxic waste for incineration at 1100°C". The material should be incinerated at 1100°C for at least one second. Clean the area with plenty of water.

The disposal of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.

Recommended treatment in case of overdose

In case of accidental overdose of methotrexate, folic acid is indicated to reduce and counteract its toxic effects. The administration of folic acid should be started as soon as possible. The longer the time interval between methotrexate administration and folic acid administration, the less effective folic acid is in counteracting methotrexate toxicity. Monitoring of serum methotrexate concentration is essential to determine the optimal dose and duration of treatment with folic acid. In case of massive overdose, hydration and alkalization of the urine will be necessary to prevent precipitation of methotrexate or its metabolites in the renal tubules. Neither standard hemodialysis nor peritoneal dialysis has shown a clear improvement in methotrexate elimination. However, effective clearance of methotrexate has been reported with intermittent acute dialysis using a high-flow dialyzer.

In case of accidental intrathecal overdose, intensive systemic support, high-dose systemic folic acid (not intrathecal), alkaline diuresis, rapid cerebrospinal fluid drainage, and ventriculolumbar perfusion will be necessary.

In general, the dose of folic acid should be administered by IV infusion in doses of up to 75 mg in the first 12 hours, followed by folic acid 15 mg orally or IV every 6 hours for at least 4 doses until serum methotrexate levels are less than 5 x 10-7 M.