Package Insert: Information for the User

Methotrexate Pfizer 25 mg/ml Injectable Solution EFG

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, pharmacist, or nurse.
• This medication has been prescribed only for you, 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, pharmacist, or nurse, even if they are not listed in this package insert. See section 4.

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

2.What you need to know before starting to use Methotrexate Pfizer

3.How to use Methotrexate Pfizer

4.Possible adverse effects

5Storage of Methotrexate Pfizer

6.Contents of the package and additional information

Metotrexato belongs to a group of medications known as folate analog antimetabolites.

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

Metotrexato is indicated for the treatment of various malignant diseases such as choriocarcinoma (development of a tumor directly associated with pregnancy), acute leukemia, breast cancer, head and neck cancer, urinary bladder cancer, osteogenic sarcoma (bone cancer) and malignant lymphomas. It is also indicated to prevent and treat leukemic meningitis (leukemic infiltration in the central nervous system).

It is also used in the treatment of severe rheumatoid arthritis; in the treatment of juvenile idiopathic arthritis, psoriasis and psoriatic arthritis (only when necessary and other treatments have failed).

It is also indicated for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation.

Before starting to use this medication, you must 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 severe diseases, including death.

Do not use Metotrexato Pfizer:

• If you are allergic to methotrexate or to any of the other components of this medication(listed in section 6).
• If you have liver function disorders (hepatic insufficiency).
• If you have severe kidney function disorders (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 disorders (immunodeficiency syndromes).
• Severe, acute, or chronic infections such as tuberculosis and HIV.
• If you have mouth, stomach, or intestinal ulcers.
• If you are to be vaccinated.
• If you are breastfeeding.

Additionally, 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 Metotrexato Pfizer.

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 are 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.
• If you do not follow the dosage scrupulously as indicated by your doctor, for example, a weekly prescribed dose that is administered by mistake daily, it may lead to toxicity, even fatal.
• It is not recommended to use it in the treatment of neoplastic diseases in women (cancer) at risk of pregnancy, 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 experience 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 a peptic ulcer 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 alterations may require closer monitoring by your doctor but do not lead to the suspension of treatment. Alcohol, obesity, advanced age, and 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 to be vaccinated, as it may cause a 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, abnormal behavior, and localized alterations in 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 the skin from intense sunlight, wear suitable clothing or use a high-protection sunscreen.
• A severe pulmonary hemorrhage has been reported 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 thinking, 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. Additionally, your blood will be checked for serum albumin (a protein in the blood), liver infection (hepatic infection), and kidney 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 will also check if you have tuberculosis and may 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 kidney 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 notable, 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 kidney function related to age, as well as the low body reserves of vitamin acid folic in old age, require a relatively low dose of methotrexate.

Other medications and Metotrexato Pfizer

Inform your doctor or pharmacist if you are using or have used recently or may need to use any other medication.

Certain medications may interact with methotrexate:

• 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 digestive tract ulcers).
• Leflunomide (medication for the treatment of 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, aminobenzoic 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 the treatment of asthma).
• Vitamins or vitamin preparations containing folic acid or its derivatives.
• Nitrous oxide (anesthetic).
• Amiodarone (medication 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 (methoxalen 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 transfusion of red blood cells.

Use of Metotrexato with food, drinks, and alcohol

While using methotrexate, you should avoid consuming alcohol, as this may increase the likelihood of adverse effects, especially in the liver. Your 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, damage the fetus, or cause abortions. It is associated with skull, face, heart, and blood vessel malformations, brain, and limb malformations. Therefore, it is very important that it is not administered to pregnant women or those planning to become pregnant, except if it is used as oncological treatment.

In non-oncological indications (not related to cancer) in fertile women, 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 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 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 starting treatment.

• Fertility in men:

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, it is recommended that men treated with methotrexate doses higher than 30 mg/week consider preserving semen 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 operating machinery

It is not recommended to drive vehicles or operate machinery after administering Metotrexato Pfizer, as some of the possible adverse effects, such as dizziness and fatigue, may affect your ability to drive vehicles and operate machinery.

Metotrexato Pfizer contains sodium

This medication contains less than 1 mmolof sodium (23 mg) per milliliter (ml); this is, essentially “sodium-free”.

Metotrexato should only be prescribed by experienced doctors who are familiar with the use of metotrexato and have a thorough understanding of the risks associated with metotrexato treatment.

Follow exactly the administration instructions for this medication as indicated by your doctor or pharmacist. If in 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 based on your condition and response to treatment.

When high doses of metotrexato are administered, your doctor may prescribe a vitamin called folic acid for you to take in the following days to prevent medication side effects. It is very important that you take the folic acid doses as instructed by your doctor. Your doctor may also advise you to drink plenty of fluids to prevent possible kidney problems.

If you take more Metotrexato Pfizer than you should

Although unlikely, if you receive more metotrexato than you should, it is recommended to administer folic acid as soon as possible, as well as hydrate and alkalize your urine. You may also experience some known side effects of the medication.

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

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 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,reactions similar to sunburn due to increased skin sensitivity to sunlight
• brown discoloration of the skin, hair loss, increased number of rheumatoid nodules, herpes zoster, 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), pain while 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 movement, sometimes limited to the right or left side of the body
• important visual changes
• 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 stools, inflammation of the gums, digestive problems
• acute hepatitis (inflammation of the liver)
• change in nail color, acne, red or purple spots due to bleeding in blood vessels
• psoriasis worsening during radiation therapy
• skin lesions similar to sunburn or radiation-induced dermatitis
• bone fractures
• renal insufficiency, decreased or absent urine production, abnormal levels of electrolytes 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)
• 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 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, damage to the retina of the eye
• 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, damage to blood vessels in the skin, allergic inflammation of blood vessels
• protein in the urine
• decreased libido, erectile dysfunction, vaginal discharge, infertility, breast enlargement in men (gynecomastia)
• fever.

Frequency unknown(cannot be estimated from available data):

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

*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 the 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.

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

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. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Metotrexate Pfizer Composition

• The active ingredient is methotrexate.
• The other components are sodium chloride, sodium hydroxide, hydrochloric acid (for pH adjustment) and water for injectable preparations.

Product Appearance and Packaging Contents

Methotrexate Pfizer 25 mg/ml injectable solution EFG is presented in polypropylene vials with butyl halogenated rubber stoppers, with an aluminum capsule and a plastic "flip-off" stopper, containing 2 and 20 ml.

Marketing Authorization Holder

Pfizer, S.L.

Avda. de Europa, 20 B

Parque Empresarial La Moraleja

28108 Alcobendas (Madrid)

Spain

Responsible for Manufacturing

Pfizer Service Company BV

Hoge Wei 10

1930 Zaventem

Belgium

or

Bridgewest Perth Pharma Pty Ltd

15 Brodie Hall Drive

Technology Park

BENTLEY, WA6102

Australia

Last Review Date of this Leaflet: March 2025.

Other sources of information

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

This information is intended solely for healthcare professionals

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

Administration Form

If Methotrexate Pfizer 25 mg/ml injectable solution EFG needs to be diluted, it can be done in sodium chloride 0.9%, dextrose 5%, dextrose 10%, lactate Ringer, Ringer solution.

Methotrexate Pfizer can be administered intravenously, intramuscularly and intrathecally.

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

Methotrexate should not be mixed with other medications in the same infusion bag 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.

Methotrexate Pfizer does not contain any preservative agents. The vials are therefore 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 any preservative 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 performed in a designated area (preferably in a laminar flow cytotoxic cabinet). The work surface should be protected with absorbent, plasticized and disposable paper.
• While 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.
• Locking syringes are recommended. Also, large-diameter needles are recommended to minimize pressure and the possible formation of aerosols. Aerosols can also be reduced using a vented needle during preparation.
• Utensils used to dilute methotrexate or disposable body waste should be placed in a polyethylene bag and incinerated at 1100°C.

Waste 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 spill spread by covering it with absorbent material, such as paper, etc. Spills can be treated with sodium hypochlorite 5%. Collect all absorbent material or other used in the removal of the spill, place it in a plastic bag and identify 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 the event of accidental overdose of methotrexate, folinic acid is indicated to reduce and counteract its immediate toxic effects. The administration of folinic acid should be initiated as soon as possible. The greater the interval between the administration of methotrexate and folinic acid, the lower the effectiveness of folinic acid in counteracting methotrexate toxicity. Monitoring of serum methotrexate concentration is essential to determine the optimal dose and duration of folinic acid treatment. In the event of massive overdose, hydration and alkalization of urine should be performed to prevent precipitation of methotrexate or its metabolites in 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 acute intermittent hemodialysis using a high-flow dialyzer.

In the event of accidental intrathecal overdose, intensive systemic support, high doses of systemic folinic acid (not intrathecal), alkaline diuresis, rapid drainage of cerebrospinal fluid and ventriculolumbar perfusion should be performed.

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