PATIENT INFORMATION LEAFLET

Methotrexate Accord 25 mg/ml Injectable Solution EFG

methotrexate

Read this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you, and you should not give it to others even if they have the same symptoms of disease 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.

Metotrexato Accord contains the active ingredient metotrexate. Metotrexate is a cytostatic agent that inhibits cell growth. Metotrexate has its maximum effect on rapidly growing cells such as cancer cells, bone marrow cells, and skin cells.

Metotrexato Accord is used in the treatment of the following types of cancer:

• Acute lymphoblastic leukemia
• Leukemia prophylaxis
• Non-Hodgkin lymphoma
• Osteogenic sarcoma
• Adjuvant treatment of advanced breast cancer
• Metastatic or recurrent head and neck cancer
• Choriocarcinoma and similar trophoblastic diseases
• Advanced bladder cancer

Do not useMetotrexate Accord

• If you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6).
• If you have a serious liver disease (your doctor will determine the severity of your disease).
• If you have a serious kidney disease (your doctor will determine the severity of your disease).
• If you have blood cell disorders.
• If you have a severe or pre-existing infection, such as tuberculosis and HIV.
• If you have mouth, throat, or gastrointestinal ulcers.
• If you are breastfeeding and also, in non-oncological indications (non-cancer treatment) if you are pregnant (see section Pregnancy, breastfeeding and fertility).
• If you have a high alcohol consumption.

Do not receive live vaccines during treatment with Metotrexate Accord.

Inform your doctor before using Metotrexate Accord if you think any of the above symptoms apply to your case.

Warnings and precautions

• Methotrexate can cause severe and potentially life-threatening adverse reactions. Your doctor will discuss the benefits and risks of treatment and the early signs and symptoms of adverse reactions.
• Methotrexate can cause a decrease in cells responsible for immunity, oxygen transport, and normal blood clotting, increasing the risk of infections (e.g. pneumonia) or bleeding.
• Acute pulmonary hemorrhage has been reported with methotrexate in patients with underlying rheumatic disease. If you experience symptoms of coughing or spitting up blood, contact your doctor immediately.Methotrexate temporarily affects sperm and egg production. Due to the risk of infertility, it is recommended that male patients consider preserving their sperm before starting treatment.
• Methotrexate can cause miscarriages and severe birth defects. If you are a woman, avoid pregnancy during treatment with methotrexate and for at least 6 months after its completion. If you are a man, avoid fathering a child during treatment with methotrexate and for at least 3 months after its completion. See also the section "Pregnancy, breastfeeding and fertility".
• Methotrexate can make your skin more sensitive to sunlight. Avoid intense sunlight and do not use sunbeds or solar lamps without medical advice. To protect your skin from intense sunlight, wear suitable clothing or use a high-factor sunscreen.

Speak to your doctor, pharmacist, or nurse before taking Metotrexate Accord:

• If you are receiving radiation therapy at the same time as treatment with methotrexate. The risk of tissue and bone damage may increase with simultaneous treatment.
• If you are receiving treatment through the spinal cord (intrathecal) or a vein (intravenous), this treatment may cause potentially fatal brain inflammation.
• If you have a disease that causes fluid retention in the body, such as in the lungs or abdomen.
• If you have kidney function impairment.
• If you have liver function impairment.
• If you have an infection.
• If you need to be vaccinated, as methotrexate may reduce the effect of vaccines.
• If you have insulin-dependent diabetes, treatment with methotrexate should be closely monitored.

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 brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended precautions and follow-up examinations:

Even when used at low doses, methotrexate can cause severe side effects. To recognize them in time, your doctor should perform checks and laboratory tests.

Before starting treatment:

Before starting treatment, your doctor may perform blood tests and check your kidney and liver function. You may also have a chest X-ray. Additional tests may be performed during and after treatment. Do not miss blood test appointments.

Other medicines and Metotrexate Accord

Inform your doctor or pharmacist if you are taking, have recently taken, or may take other medicines, as methotrexate affects or is affected by some medicines used for:

• Pain and inflammation (NSAIDs and salicylates)
• Cancer (cisplatin, cytarabine, mercaptopurine, fluorouracil)
• Infections (antibiotics such as penicillins, tetracycline, and chloramphenicol)
• Asthma (theophylline)
• Vitamin preparations with folic acid or similar substances
• Rheumatism (leflunomide)
• Hypertension (furosemide)
• Gout (probenecid)
• Radiation therapy
• Stomach ulcers, heartburn, and reflux (e.g. omeprazole, pantoprazole, lansoprazole)
• Epilepsy (phenytoin)
• Severe psoriasis or acne (retinoids, such as acitretin or isotretinoin)
• Rheumatoid arthritis or intestinal disease (sulfasalazine)
• Organ transplant rejection (azathioprine)
• Live vaccines
• Nitrous oxide ("laughing gas" inhaled to relieve pain)
• Barbiturates (a group of medicines used as hypnotics, sedatives, anesthetics, or anticonvulsants)
• Tranquilizers
• Hypoglycemic agents (used to treat diabetes)
• Pyrimethamine (used to prevent and treat malaria)
• Oral contraceptives
• Metamizole (synonyms novaminsulfon and dipyrone) (pain reliever and fever reducer).

Metotrexate Accord with food, drinks, and alcohol

During treatment with Metotrexate Accord, do not drink alcohol and avoid excessive consumption of coffee, caffeinated soft drinks, and black tea. Also, make sure to drink plenty of fluids during treatment with Metotrexate Accord, as dehydration (reduction of body water) may increase the toxicity of Metotrexate Accord.

Pregnancy, breastfeeding, and fertility

Pregnancy

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

Do not use Metotrexate Accord during pregnancy except if your doctor has prescribed it as an oncological treatment. Methotrexate can cause birth defects, harm the fetus, or cause miscarriages. It is associated with skull, face, heart, and blood vessel malformations, brain, and limb defects. 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 an oncological treatment.

In non-oncological indications in fertile women, any possibility of pregnancy should be excluded, for example, by a pregnancy test, before starting treatment.

Do not use Metotrexate Accord 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 the 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.

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 ruled out completely, and there is no information on higher doses of methotrexate. Methotrexate may be genotoxic, meaning it can cause genetic mutations. Methotrexate may affect sperm production, which is associated with the risk of birth defects.

Therefore, you should avoid fathering a child or donating sperm 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 above 30 mg/week consider preserving their sperm before starting treatment (see also the section "Warnings and precautions").

Breastfeeding

Methotrexate is excreted in breast milk in amounts that pose a risk to the baby. Therefore, you should stop breastfeeding before starting treatment with methotrexate.

Driving and operating machinery

You may experience side effects such as fatigue and dizziness. If you feel tired or dizzy, do not drive or operate machinery.

Metotrexate Accord contains sodium

This medicine contains 345.59 mg of sodium (main component of table salt/for cooking) in its maximum recommended daily dose. This is equivalent to 17.27% of the maximum recommended daily sodium intake for an adult.

Metotrexato Accord is provided by healthcare professionals.

The dose you receive and the frequency of administration will depend on the disease being treated, your health status, age, weight, and body surface area. Metotrexato Accord can be taken orally or injected into a muscle (intramuscular), a vein (intravenous), an artery (intraarterial), or the spinal cord (intrathecal).

Metotrexato should not come into contact with the skin surface or mucous membranes. In case of contamination, the affected area should be washed immediately with plenty of water.

Your doctor may instruct you to take sodium bicarbonate or acetazolamide tablets while receiving the medication to help prevent the metotrexato from concentrating in the kidneys. If you receive high doses of metotrexato, you will also receive calcium folinate to reduce the side effects of metotrexato.

If you use more Metotrexato Accord than you should

Your doctor determines the dose, which is administered by healthcare personnel. Therefore, it is unlikely that an overdose will occur. A metotrexato overdose can lead to severe toxic reactions. Symptoms of an overdose may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, vomiting with blood or black or bloody stools. The antidote for an overdose is calcium folinate.

If you forget or stop using Metotrexato Accord

You should not interrupt or discontinue treatment with Metotrexato Accord unless you have consulted with your doctor. If you forget your appointment for the next dose, contact your doctor as soon as possible to schedule a new appointment. If you suspect the presence of severe side effects, contact your doctor immediately for advice.

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. Metotrexate Accord may have side effects that can be dangerous or potentially fatal. During treatment, you should be alert to signs of side effects and report them to your doctor.

Consult a doctorimmediatelyif you experience any of the following adverse reactions. You may require immediate medical attention.

• Unexplained difficulty breathing, dry cough or wheezing (symptoms of lung problems).
• Sudden itching, skin rash (urticaria); swollen hands, feet, ankles, face, lips, mouth, and throat (which may make it difficult to breathe and swallow). You may also feel like you are about to faint (symptoms of severe allergic reaction).
• Vomiting, diarrhea, or mouth and stomach ulcers (symptoms of gastrointestinal effects).
• Yellowing of the skin or eyes, dark urine (symptoms of liver effects).
• Fever, chills, body aches, and sore throat (symptoms of infection).
• Unexpected bleeding (e.g., bleeding gums, dark urine, blood in urine or vomit) or unexpected bruises, black stools (may be due to reduced clotting ability or gastrointestinal bleeding).
• Skin rash with scales or blisters and effects on mucous membranes, e.g., in the nose (symptoms of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme).
• Abnormal behavior, transient blindness, and generalized seizures (symptoms of central nervous system effects).
• Paralysis (paresis).

The following is a list of adverse reactions reported in the treatment with metotrexate, based on their frequency.

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

• Loss of appetite, nausea, vomiting, abdominal pain, and altered digestion
• Inflammation and ulceration in the mouth and throat
• Increased activity of liver enzymes

Common (may affect more than 1 in 100 people):

• Herpes zoster
• Effects on the blood, e.g., anemia, leukopenia, thrombocytopenia
• Headache, fatigue, drowsiness
• Dry cough, difficulty breathing, chest pain, fever
• Diarrhea
• Rashes, redness, and itching

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

• Pancytopenia, agranulocytosis
• Vascular inflammation
• Anaphylactoid reactions and allergic vasculitis
• Dizziness, confusion, depression
• Seizures, encephalopathy
• Lymphoma (tumor in the lymphatic tissue)
• Pulmonary fibrosis
• Gastrointestinal bleeding and ulcers
• Pancreatitis
• Liver fibrosis and cirrhosis, hepatic steatosis
• Diabetic complications
• Reduced albumin levels
• Reactions similar to sunburn due to increased skin sensitivity to sunlight.
• Urticaria
• Increased skin pigmentation
• Hair loss, herpes zoster, painful scaly lesions due to psoriasis
• Increased rheumatoid nodules (lumps in tissues)
• Severe effects on the skin and mucous membrane (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Bladder inflammation and ulcers, hematuria, dysuria
• Vaginal inflammation and ulcers
• Osteoporosis, arthralgia, myalgia

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

• Pericarditis, pericardial effusion, cardiac tamponade
• Megaloblastic anemia
• Mood changes
• Paralysis
• Speech disorders, including dysarthria and aphasia
• Myleopathy
• Visual disturbances, blurred vision
• Thrombosis (cerebral, deep vein, and retinal vein)
• Low blood pressure
• Pharyngitis, apnea, bronchial asthma
• Gingivitis
• Small intestine inflammation
• Blood in stool
• Malabsorption
• Liver damage
• Acne, skin lesions, altered nail pigmentation, hematomas
• Fractures
• Renal insufficiency, oliguria, azotemia, and anuria
• Hyperuricemia
• Increased serum creatinine and urea levels
• Abnormal development of mammary glands
• Elevated blood sugar levels (diabetes mellitus)

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

• Infections, septicemia, opportunistic infections
• Severe bone marrow insufficiency, aplastic anemia (due to the bone marrow's inability to produce blood cells), lymphadenopathy, lymphoproliferative disorders (excessive increase in white blood cells), eosinophilia, and neutropenia
• Immunosuppression
• Hypogammaglobulinemia
• Insomnia
• Cognitive impairment, including thinking, remembering, or reasoning
• Joint or muscle pain, lack of strength
• Myasthenia (muscle weakness)
• Abnormal sensations, altered sense of taste (metallic taste)
• Meningism (paralysis, vomiting), acute aseptic meningitis
• Conjunctivitis, retinopathy, vision loss, swollen eye
• Inflammation, follicles, epiphora, and photophobia
• Tumor lysis syndrome
• Pulmonary function problems, difficulty breathing, pneumonia
• Pulmonary infections
• Pleural effusion
• Toxic megacolon
• Reactivation of chronic hepatitis, acute liver degeneration, herpes simplex, hepatitis, liver insufficiency
• Painful swelling of the skin around the nails
• Expansion of small blood vessels in the skin (paronychia)
• Allergic vasculitis, hidradenitis
• Proteinuria
• Loss of libido, impotence
• Menstrual disorders
• Vaginal discharge
• Infertility
• Fever, altered wound healing

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

• Bleeding, blood vessel rupture
• Psychosis
• Accumulation of fluid in the brain and lungs
• Metabolic disorder
• Necrotic skin, exfoliative dermatitis
• Fractures of the jaw bones (secondary to excessive increase in white blood cells)
• Redness and peeling of the skin

If you receive Metotrexate Accord in the spinal cord, the following adverse reactions are common (may affect up to 1 in 100 people):

• Headache
• Fever
• Inflammation of the arachnoid membrane of the brain and spinal cord, which can cause neck stiffness, vomiting, fever, and altered general health, which may occur within hours of receiving the metotrexate injection, but usually resolves within days.
• Paralysis or total weakness, weakness in one or all extremities, and muscle cramps (which usually occur after repeated metotrexate injections in the spinal cord)
• Neurological effects that may begin with confusion, irritability, and fatigue. It may worsen over time and lead to dementia (memory loss, disorientation, and confusion), speech disorders, coordination and balance difficulties, increased muscle stiffness, muscle cramps, and coma. This condition may occur several months or years after starting metotrexate treatment injected into the spinal cord. The condition can be potentially fatal and occurs mainly when large amounts of metotrexate are administered in the spinal cord in combination with head radiation or metotrexate in some other form.

Reporting of adverse effects:

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use: https://www.notificaRAM.es. By reporting adverse 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 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.

Store below 25°C.

Vial after the first opening – Use immediately after opening.

After dilution – 24 hours

The physical and chemical stability of the diluted solution has been demonstrated for 24 hours. From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the storage and conservation conditions before use will be the responsibility of the user and normally will not exceed 24 hours at 2-8°C, unless the reconstitution/dilution is carried out in controlled and validated aseptic conditions.

Do not throw away the medications through the drains or in the trash. Ask your pharmacist where to dispose of the unused medications. In this way, you will help protect the environment.

Metotrexate Accord Composition

• The active ingredient is methotrexate. 1 ml of solution contains 25 mg of methotrexate.
• The other components are sodium chloride, sodium hydroxide/hydrochloric acid (for pH adjustment) and water for injection preparations.

Appearance of the product and contents of the pack

The medicine is a yellow and transparent solution.

Pack size:1 vial for pack sizes of 2 ml, 20 ml and 40 ml

10 vials for pack sizes of 20 ml and 40 ml

Only some pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6th floor

08039 Barcelona

Spain

Responsible Person

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow, Middlesex

HA1 4HF,

UK

or

Accord Healthcare Polska Sp.z o.o.,

ul. Lutomierska 50,95-200 Pabianice, Poland

or

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

Netherlands

This medicinal product is authorised in the Member States of the EEA under the following names

Last review date of this leaflet: January 2025

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

Information intended exclusively for healthcare professionals:

Instructions for preparation, handling and disposal of Methotrexate Accord 25 mg/ml injectable solution

The solution must be visually inspected before use. It should only be used if the solution is practically transparent and free of particles.

Methotrexate injection may be diluted with an appropriate medium without preservatives such as 5% glucose solution or 0.9% sodium chloride.

The following general recommendations should be considered with regard to handling: The product should be used and administered only by experienced personnel; the mixing of the solution should take place in designated areas, designed to protect personnel and the environment (e.g. safety cabinets); protective clothing (including gloves, eye protection and masks if necessary) should be worn.

Healthcare professionals who are pregnant should not handle and/or administer Methotrexate Accord.

Methotrexate should not come into contact with the skin or mucous membranes. In the event of contamination, the affected area should be washed immediately with copious amounts of water for at least 10 minutes.

For single use only. Any unused solution should be discarded. Residues should be disposed of carefully in suitable separate containers, clearly labelled according to their content (such as patient bodily fluids or excreta which may also contain significant amounts of antineoplastic agents and it is suggested that such material, as well as contaminated bedding, should also be treated as hazardous waste). The disposal of unused medicinal product will be carried out in accordance with local regulations by incineration.

There should be adequate procedures for accidental contamination due to spillage, exposure of personnel to antineoplastic agents should be inspected and recorded.