METOTREXATE ACCORD 100 mg/mL concentrate for infusion solution

2. What you need to know before you use Metotrexato Accord

Do not useMetotrexato Accord

• If you are allergic to metotrexato 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 disorders of the system that forms blood cells.
• If you have a severe or pre-existing infection, such as tuberculosis or HIV.
• If you have ulcers in the mouth and throat or gastrointestinal ulcers.
• If you are breastfeeding and also, in non-oncological indications (treatment not related to cancer) if you are pregnant (see section Pregnancy, breastfeeding and fertility).
• If you have a high consumption of alcohol.

You should not receive live vaccines during treatment with Metotrexato Accord.

Tell your doctor before using Metotrexato Accord if you think any of the above applies to your case.

Warnings and precautions

• Metotrexato can cause serious and potentially life-threatening side effects. Your doctor will discuss the benefits and risks of treatment and what the early signs and symptoms of side effects are.
• Metotrexato can cause a decrease in cells responsible for immunity, oxygen transport, and those responsible for normal blood coagulation, resulting in an increased risk of infections (e.g., pneumonia) or bleeding.
• Acute pulmonary hemorrhage has been reported with metotrexato in patients with underlying rheumatologic disease. If you experience symptoms of coughing or spitting blood, contact your doctor immediately.
• Metotrexato affects sperm and egg production temporarily. Because treatment with metotrexato can cause infertility, it is advisable for male patients to consider preserving their sperm before starting treatment.
• Metotrexato can cause abortions and severe birth defects. If you are a woman, you should avoid pregnancy during treatment with metotrexato and for at least 6 months after treatment ends. If you are a man, you should avoid fathering a child during treatment with metotrexato and for at least 3 months after treatment ends. See also section "Pregnancy, breastfeeding and fertility".
• Metotrexato can make your skin more sensitive to sunlight. Avoid intense sunlight and do not use sunbeds or sunlamps without medical advice. To protect your skin from intense sunlight, wear suitable clothing or use a sunscreen with a high protection factor.

Talk to your doctor, pharmacist, or nurse before taking Metotrexato Accord:

• If you are receiving radiotherapy at the same time as treatment with metotrexato. The risk of tissue and bone damage may increase with concurrent treatment.
• If you are receiving treatment through the spinal cord (intrathecal) or a vein (intravenous), this treatment can cause potentially life-threatening inflammation in the brain.
• 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 metotrexato can reduce the effect of vaccines.
• If you have insulin-dependent diabetes, treatment with metotrexato should be closely monitored.

If you, your partner, or your caregiver notice the onset 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 because these can be symptoms of a rare and serious brain infection called progressive multifocal leukoencephalopathy (PML).

Precautions and recommended follow-up exams:

Even when metotrexato is used in low doses, serious side effects can occur. 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 also check the functioning of your kidneys and liver. You may also have a chest X-ray. More tests may be performed during and after treatment. Do not miss appointments for blood tests.

Other medicines and Metotrexato Accord

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

• Pain and inflammation (so-called 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)
• Radiotherapy
• Stomach ulcers, heartburn, reflux (such as omeprazole, pantoprazole, lansoprazole)
• Epilepsy (phenytoin)
• Psoriasis or severe acne (retinoids, such as acitretin or isotretinoin)
• Rheumatoid arthritis or intestinal disease (sulfasalazine)
• Organ transplant rejection (azathioprine)
• If you need to be vaccinated with a live vaccine
• Nitrous oxide ("laughing gas" inhaled for pain relief)
• 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) (medicine for severe pain and/or fever).

Metotrexato Accord with food, drinks, and alcohol

During treatment with Metotrexato Accord, you should not drink alcohol and should avoid excessive consumption of coffee, caffeinated soft drinks, and black tea. Also, make sure to drink plenty of fluids during treatment with Metotrexato Accord, as dehydration (reduction of body water) can increase the toxicity of Metotrexato 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 Metotrexato Accord during pregnancy unless your doctor has prescribed it as an oncological treatment. Metotrexato 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 planning to become pregnant, unless it is used as an oncological treatment.

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

Do not use Metotrexato Accord if you are trying to become pregnant. You should avoid becoming pregnant while taking metotrexato and for at least 6 months after treatment ends. 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 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 metotrexato less than 30 mg/week. However, this risk cannot be completely ruled out, and there is no information on higher doses of metotrexato. Metotrexato can be genotoxic, which means it can cause genetic mutations. Metotrexato can affect sperm production, which is associated with the possibility of birth defects.

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

Breastfeeding

Metotrexato is excreted in breast milk in amounts that pose a risk to the baby. Therefore, breastfeeding should be discontinued before treatment with metotrexato.

Driving and using machines

Side effects such as fatigue and dizziness can occur. If you feel tired or dizzy, do not drive or use machinery.

Metotrexato Accord contains sodium

This medicine contains 194 mg of sodium (the main component of cooking/table salt) in its maximum recommended daily dose. This is equivalent to 9.7% of the maximum recommended daily intake of sodium for an adult.

3. How to use Metotrexato Accord

Metotrexato Accord is provided by healthcare professionals.

The dose you receive and the frequency of administration will depend on the disease being treated, your state of health, and your age, weight, and body surface area. Metotrexato Accord can be administered by injection into a muscle (intramuscular), into a vein (intravenous), or into an artery (intraarterial). Metotrexato Accord must not be injected into the spinal cord (intrathecal).Higher doses are usually administered by infusion over 24 hours, alone or in combination with other medicines used to treat cancer.

Metotrexato should not come into contact with the skin 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 medicine to help prevent metotrexato from concentrating in the kidneys. If you receive high-dose 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 decides the dose, which is administered by healthcare personnel. Therefore, it is unlikely that an overdose will occur. An overdose of metotrexato can lead to serious toxic reactions. Symptoms of overdose may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, vomiting blood or black or tarry stools. The antidote in case of overdose is calcium folinate.

If you forget to use Metotrexato Accord

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

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. Metotrexato Accord may have adverse effects that can be hazardous or potentially fatal. During treatment, you should be alert to signs of adverse effects and report them to your doctor.

Contact a doctor immediately if you experience any of the following adverse reactions. You may need 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 can make breathing and swallowing difficult). You may also feel like you are about to faint (symptoms of severe allergic reaction).
• Vomiting, diarrhea, or stomatitis and peptic ulcers (symptoms of effects on the digestive tract).
• Yellowing of the skin or eyes, dark-colored urine (symptoms of effects on the liver).
• Fever, chills, body pain, and throat irritation (symptoms of infection).
• Unexpected bleeding (e.g., bleeding gums, dark urine, blood in urine or vomit) or unexpected bruising, black tarry stools (may be due to a reduction in blood 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 effects on the central nervous system).
• Paralysis (paresis).

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

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

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

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

• 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 person in 100):

• Pancytopenia, agranulocytosis
• Inflammation of blood vessels
• Anaphylactoid reactions and allergic vasculitis
• Dizziness, confusion, depression
• Seizures, encephalopathy
• Lymphoma (tumor in lymphatic tissue)
• Pulmonary fibrosis
• Bleeding and ulcers in the stomach and intestine
• Inflammation of the pancreas
• Hepatic 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 plaque lesions due to psoriasis
• Increased rheumatoid nodules (lumps in tissues)
• Effects on the skin and mucous membrane, which can be severe (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Inflammation and ulceration of the bladder, hematuria, dysuria
• Inflammation and ulcers of the vagina
• Brittle bones (osteoporosis), arthralgia, myalgia

Rare (may affect up to 1 person in 1,000)

• Pericarditis, pericardial effusion, pericardial tamponade
• Megaloblastic anemia
• Mood changes
• Paresis
• Affectation of speech, including dysarthria and aphasia
• Myelopathy
• Visual disturbances, blurred vision
• Thrombosis (cerebral, deep vein, and retinal vein)
• Hypotension
• Pharyngitis, apnea, bronchial asthma
• Gingivitis
• Inflammation of the small intestine
• Blood in the stool
• Malabsorption
• Liver damage
• Acne, skin ulcers, alteration of nail pigment, bruising
• Fractures
• Renal failure, oliguria, azotemia, and anuria
• Hyperuricemia
• Increased serum creatinine and urea concentration
• Abnormal development of mammary glands
• Elevated blood sugar levels (diabetes mellitus)

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

• Infections, septicemia, opportunistic infections
• Severe bone marrow failure, 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
• Affectation of intellectual functions such as thinking, remembering, or reasoning
• Joint or muscle pain, lack of strength
• Myasthenia (muscle weakness)
• Abnormal sensations, alterations in taste (metallic taste)
• Meningism (paralysis, vomiting), aseptic meningitis
• Conjunctivitis, retinopathy, vision loss, swollen eye
• Inflammation, eye follicles, epiphora, and photophobia
• Tumor lysis syndrome
• Pulmonary function problems, difficulty breathing, pneumonia
• Pulmonary infections
• Pleural effusion
• Colon dilation (toxic megacolon)
• Reactivation of chronic hepatitis, acute liver degeneration, simple herpes, hepatitis, liver failure
• 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, alteration of wound healing

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

• Bleeding, blood leakage from vessels
• Psychosis
• Fluid accumulation in the brain and lungs
• Metabolic disorder
• Necrosis of the skin, exfoliative dermatitis
• Lesion in the jawbone (secondary to excessive increase in white blood cells)
• Redness and peeling of the skin

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

• Headache
• Fever
• Inflammation of the arachnoid membrane of the brain and spinal cord that can cause back pain, neck stiffness, vomiting, fever, and alteration of general health, which can occur within hours of receiving the metotrexate injection but usually disappears within a few days.
• Hemiplegia or total paralysis, weakness in one or all limbs, and cramp attacks (which normally occur after repeated injection of metotrexate into the spinal cord)
• Effect on the nervous system that can start with confusion, irritation, and fatigue. It can worsen over time and lead to dementia (increased memory loss, disorientation, and confusion), speech disorders, coordination and balance difficulties, increased muscle stiffness, cramps, and coma. This condition can occur several months or years after starting treatment with metotrexate 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 radiation therapy in the head or metotrexate in another 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 Pharmacovigilance System for Human Use Medicines: https://www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Metotrexato Accord

Keep this medicine out of sight and reach of children.

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

Do not store at a temperature above 30°C.

Vial after first opening – Use immediately after opening.

After dilution

Physical and chemical stability of the diluted solution in glucose solution (5%) and sodium chloride solution (0.9%) at concentrations of 5 mg/ml and 20 mg/ml has been demonstrated for 36 hours at 20-25°C and 35 days at 2-8°C. The diluted product is stable in both diluents and in both concentrations for 36 hours at 20-25°C and 35 days at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the conditions and storage periods before use will be the responsibility of the user and should not exceed 24 hours at 2-8°C, unless the dilution takes place in validated and controlled aseptic conditions.

Do not throw away medicines through sewage or trash. Ask your pharmacist where to throw away medicines that are no longer used. This way, you will help protect the environment.

6. Package Contents and Additional Information

Composition of Metotrexato Accord

• The active ingredient is metotrexate.
• 1 ml of solution contains 100 mg of metotrexate.

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

Appearance of the Product and Package Contents

The medicine is a clear yellow solution.

Package size: 1 vial for package sizes of 5 ml, 10 ml, and 50 ml

10 vials for package sizes of 5 ml, 10 ml, and 50 ml

Only some package sizes may be marketed.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6ª planta

08039 Barcelona

Spain

Manufacturer

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow, Middlesex

HA1 4HF,

United Kingdom

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 pharmaceutical product is authorized in the EEA member states under the following names

Date of last revision of this prospectus: January 2025

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

Information intended exclusively for medical or healthcare professionals:

Instructions for Preparation, Handling, and Disposal of Metotrexato Accord 100 mg/ml Concentrate for Solution for Perfusion

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

The metotrexate injection can be diluted with a suitable medium without preservatives, such as glucose solution (5%) or sodium chloride solution (0.9%). Physical and chemical stability of the diluted solution in glucose solution (5%) and sodium chloride solution (0.9%) at concentrations of 5 mg/ml and 20 mg/ml has been demonstrated for 36 hours at 20-25°C and 35 days at 2-8°C. The diluted product is stable in both diluents and in both concentrations for 36 hours at 20-25°C and 35 days at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the conditions and storage periods before use will be the responsibility of the user and should not exceed 24 hours at 2-8°C, unless the dilution takes place in validated and controlled aseptic conditions.

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 should be worn (including gloves, eye protection, and masks if necessary).

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

Metotrexate should not come into contact with the skin or mucous membranes. In case of contamination, the affected area should be rinsed immediately with copious amounts of water for at least ten minutes.

For single use. Any unused solution should be discarded. Waste should be disposed of carefully in separate, clearly labeled containers according to their content (such as patient bodily fluids or excreta that 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 medicine will be carried out in accordance with local regulations by incineration.

There should be adequate procedures for accidental contamination due to spills, and personnel exposure to antineoplastic agents should be inspected and archived.