Metotreksat Accord

Leaflet accompanying the packaging: information for the user

Metotreksat Accord, 100 mg/ml, concentrate for solution for infusion

Methotrexate

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor, pharmacist or nurse.
• This medicine has been prescribed specifically for you. Do not pass it on to others. The medicine may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any possible side effects not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Metotreksat Accord and what is it used for
• 2. Important information before using Metotreksat Accord
• 3. How to use Metotreksat Accord
• 4. Possible side effects
• 5. How to store Metotreksat Accord
• 6. Contents of the packaging and other information

1. What is Metotreksat Accord and what is it used for

The active substance of Metotreksat Accord is methotrexate. Methotrexate is a cytostatic medicine that inhibits cell growth. Methotrexate has the greatest effect on rapidly dividing cells, such as cancer cells, bone marrow cells, and skin cells. Metotreksat Accord is used to treat the following types of cancer:

• acute lymphoblastic leukemia,
• non-Hodgkin's lymphoma,
• osteosarcoma,
• as an adjunct in advanced breast cancer,
• head and neck cancer with metastasis or recurrence,
• choriocarcinoma and other types of trophoblastic disease,
• advanced bladder cancer.

2. Important information before using Metotreksat Accord

When not to useMetotreksat Accord

• if the patient is allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6),
• if the patient has severe liver or kidney disease,
• if the patient abuses alcohol,
• if the patient has blood disorders,
• if the patient has severe infections, such as tuberculosis and HIV,
• if the patient has ulcers in the mouth and throat or peptic ulcer disease,
• if the patient is breastfeeding (see section: Pregnancy, breastfeeding and fertility).

Do not take live vaccines while using Metotreksat Accord. Tell your doctor before using Metotreksat Accord if any of the above applies to you.

Warnings and precautions

• Methotrexate can cause serious, sometimes life-threatening side effects. The doctor will discuss the benefits and risks of treatment with the patient and early signs of side effects.
• Methotrexate may reduce the number of cells responsible for immunity, carrying oxygen, and blood clotting, increasing the risk of infection (e.g., pneumonia) or excessive bleeding.
• During methotrexate treatment, cases of acute bleeding from the lungs have been reported in patients with underlying rheumatologic disease. If the patient experiences symptoms such as coughing up blood or bloody sputum, they should contact their doctor immediately.
• Methotrexate can temporarily disrupt sperm and egg production. Methotrexate treatment may lead to infertility; therefore, male patients should consider the possibility of sperm cryopreservation before starting treatment. Methotrexate may cause miscarriage and severe birth defects. Female patients should avoid becoming pregnant while taking methotrexate and for at least 6 months after treatment. Male patients should avoid impregnating their partner while taking methotrexate and for at least 3 months after treatment. See also the section "Pregnancy, breastfeeding and fertility".
• Methotrexate may increase skin sensitivity to sunlight. Avoid intense sunlight and do not use a sunbed or sunlamp without consulting a doctor. To protect the skin from intense sunlight, wear appropriate clothing or use a sunscreen with a high protection factor.

Before starting Metotreksat Accord, discuss the following with your doctor, pharmacist or nurse:

• if the patient will be undergoing radiation therapy at the same time as methotrexate treatment. Concurrent treatment may increase the risk of tissue and bone damage,
• if the patient is receiving intrathecal (intracanal) or intravenous treatment, it may cause potentially life-threatening meningitis. Metotreksat Accord 100 mg/ml must not be administered intrathecally.
• if the patient has a condition characterized by fluid retention in the body, such as in the lungs or abdomen,
• if the patient has kidney function disorders,
• if the patient has liver function disorders,
• if the patient has an infection.
• if the patient needs to take a vaccine. Methotrexate may reduce the effectiveness of vaccines.
• if the patient has insulin-dependent diabetes, methotrexate treatment should be closely monitored.

If the patient, their partner, or caregiver notices new onset or worsening of neurological symptoms, including general muscle weakness, vision disturbances, changes in thinking, memory, and orientation leading to disorientation and personality changes, they should contact their doctor immediately, as these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended monitoring and precautions during treatment:

Even when using low doses of methotrexate, serious side effects may occur. To recognize them in time, the doctor must perform monitoring and laboratory tests.

Before starting treatment:

Before starting treatment, the doctor may perform blood tests and check kidney and liver function. The patient may also have a chest X-ray. Additional tests may be performed during and after treatment. Do not forget about blood test appointments.

Metotreksat Accord and other medicines

Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, as well as any medicines you plan to take. Methotrexate interacts with or is affected by some other medicines used to treat:

• pain and inflammation (NSAIDs and salicylates),
• cancer (cisplatin, cytarabine, mercaptopurine),
• infections (ciprofloxacin and antibiotics such as penicillins, tetracyclines, and chloramphenicol),
• asthma (theophylline),
• vitamin preparations containing folic acid or substances similar to folic acid,
• rheumatism (leflunomide),
• high blood pressure (furosemide),
• gout (probenecid),
• radiation therapy,
• ulcer disease, heartburn, reflux (omeprazole, pantoprazole, lansoprazole),
• epilepsy (phenytoin),
• psoriasis or severe acne (retinoids such as acitretin or isotretinoin),
• rheumatoid arthritis or bowel disease (sulfasalazine),
• organ transplant rejection (azathioprine),
• if the patient needs to be vaccinated with a live vaccine.
• nitrous oxide ("laughing gas", inhaled to relieve pain),
• barbiturates (a group of medicines used as sleeping pills, sedatives, anesthetics, or anticonvulsants),
• sedatives,
• hypoglycemic agents (used to treat diabetes),
• pyrimethamine (used to prevent and treat malaria),
• oral contraceptives
• metamizole (synonyms: novaminsulfone and dipyrone) (a strong pain reliever and/or antipyretic).

Metotreksat Accord with food, drink, and alcohol

While using Metotreksat Accord, do not drink alcohol and avoid excessive consumption of coffee, non-alcoholic beverages containing caffeine, and black tea. During treatment, also take large amounts of fluids, as dehydration (reduced water in the body) may increase the toxicity of Metotreksat Accord.

Pregnancy, breastfeeding, and fertility

Pregnancy
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult a doctor before using this medicine.
Do not use Metotreksat Accord during pregnancy, unless the doctor has recommended it for oncological indications. Methotrexate may cause birth defects, harm the unborn child, or cause miscarriage. This is related to developmental abnormalities of the skull, face, heart, and blood vessels, brain, and limbs. Therefore, it is very important that female patients who are pregnant or planning to become pregnant do not take methotrexate, unless it is for oncological indications.
If the patient is of childbearing age, before starting treatment for non-oncological indications, it should be confirmed that she is not pregnant, e.g., by performing a pregnancy test.
Do not use Metotreksat Accord if the patient is pregnant or trying to become pregnant.
The patient should absolutely avoid becoming pregnant while taking methotrexate and for at least 6 months after treatment. During this time, effective contraception (see also the section "Warnings and precautions") is necessary.
If the patient becomes pregnant while taking methotrexate or suspects she may be pregnant, she should consult her doctor as soon as possible. If the patient becomes pregnant while taking methotrexate, she should receive advice on the possible harmful effects of treatment on the child.
If the patient plans to become pregnant, she should consult her attending doctor, who may refer her to a specialist for advice before planned treatment.
Male fertility
Available evidence does not indicate an increased risk of birth defects or miscarriages after the father takes methotrexate at a dose below 30 mg/week. However, the risk cannot be entirely ruled out; there is also 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 possibility of birth defects.
The patient should avoid impregnating his partner and donating sperm while taking methotrexate and for at least 3 months after treatment. Given that treatment with higher doses of methotrexate typically used in cancer treatment may cause infertility and genetic mutations, in the case of men treated with methotrexate at doses above 30 mg/week, it is recommended to store sperm collected before starting treatment (see also the section "Warnings and precautions").
Breastfeeding
Methotrexate passes into human milk, in amounts that pose a risk to the child.
Before starting methotrexate treatment, breastfeeding should be stopped.

Driving and using machines

Side effects such as fatigue or dizziness may occur. If the patient feels fatigued or dizzy, they should not drive vehicles or operate machines.

Metotreksat Accord contains sodium

The medicine contains 194 mg of sodium (the main component of table salt) in the maximum recommended daily dose. This corresponds to 9.7% of the recommended maximum daily sodium intake in the diet for adults.

3. How to use Metotreksat Accord

Metotreksat Accord is administered by medical personnel.
The dose and frequency of administration depend on the disease being treated, the patient's health, age, weight, and body surface area. Metotreksat Accord may be administered intramuscularly, intravenously, or intra-arterially.
Metotreksat Accord must not be administered intrathecally (into the spine).
Larger doses are usually administered as a 24-hour infusion, alone or in combination with other anticancer medicines.
Methotrexate should not come into contact with skin or mucous membranes. In case of contamination, the affected area should be rinsed immediately with a large amount of water.
The doctor may recommend taking sodium bicarbonate tablets or acetazolamide while using this medicine to ensure that methotrexate does not accumulate in the kidneys. If the patient receives methotrexate in high doses, they will also receive calcium folinate to reduce methotrexate side effects.

Using a higher dose of Metotreksat Accord than recommended

The doctor decides on the dosage, which is administered by medical personnel. Overdose is therefore unlikely. Methotrexate overdose can lead to severe toxic reactions. Symptoms of overdose may include easy bruising or bleeding, unusual weakness, mouth ulcers, nausea, vomiting, vomiting blood, and black or bloody stools. The antidote in case of overdose is calcium folinate.

Missing a dose of Metotreksat Accord

Do not stop using Metotreksat Accord unless agreed upon with your doctor.
In case of missing a visit related to taking the next dose of the medicine, contact your doctor as soon as possible and schedule the next visit. In case of suspected severe side effects, contact your doctor immediately for advice.
In case of any further doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, Metotreksat Accord can cause side effects, although not everybody gets them.
Metotreksat Accord may cause dangerous or life-threatening side effects.
During treatment, pay attention to side effects and report them to your doctor.
Contact your doctor immediately if you experience any of the following side effects. You may need urgent medical attention.

• Unexplained shortness of breath, dry cough, or wheezing (symptoms of lung disorders).
• Sudden itching, rash (hives), swelling of hands, feet, ankles, face, lips, mouth, or throat (which may make breathing and swallowing difficult). You may also feel like you are about to faint (symptoms of a severe allergic reaction).
• Vomiting, diarrhea, mouth ulcers, and gastrointestinal disease (symptoms of gastrointestinal effects).
• Yellowing of the skin and eyes, dark urine (symptoms of liver effects).
• Fever, chills, body aches, and sore throat (symptoms of infection).
• Unexpected bleeding (e.g., bruising, dark urine, blood in urine or vomit) or petechiae, black, tarry stools - may be due to limited blood clotting or bleeding in the stomach or intestines).
• Skin rashes with peeling or blisters, effects on mucous membranes, e.g., in the nose (symptoms of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme).
• Behavioral disorders, transient blindness, and generalized seizures (symptoms of central nervous system effects).
• Paralysis (paresis)

The following is a list of side effects reported during methotrexate treatment, ranked according to frequency of occurrence.
Very common (may affect more than 1 in 10 people):

• Loss of appetite, nausea, vomiting, abdominal pain, digestive disorders, indigestion
• Inflammation and ulcers of the mouth and throat
• Increased liver enzyme activity

Common (may affect up to 1 in 10 people)

• Shingles
• Effects on blood, e.g., anemia, leukopenia, thrombocytopenia
• Diarrhea
• Dry cough, shortness of breath, chest pain, fever
• Rash, redness, and itching
• Headache, fatigue, drowsiness

Uncommon (may affect up to 1 in 100 people)

• Pancytopenia, agranulocytosis
• Vasculitis
• Pseudo-anaphylactic and allergic vasculitis reactions
• Dizziness, disorientation, depression
• Seizures, encephalopathy
• Lymphoma (tumor of lymphoid tissue)
• Pulmonary fibrosis
• Bleeding and ulcers in the stomach and intestines
• Pancreatitis
• Diabetic complications
• Decreased albumin levels
• Increased skin pigmentation
• Hair loss, painful peeling skin lesions due to psoriasis
• Increased rheumatoid nodules (nodules in tissues)
• Effects on skin and mucous membranes, sometimes severe (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Reactions similar to sunburn due to increased skin sensitivity to sunlight
• Hives
• Bone fragility (osteoporosis), joint pain, muscle pain
• Fibrosis and cirrhosis of the liver, fatty liver
• Inflammation and ulcers of the bladder, hematuria, difficulty urinating
• Inflammation and ulcers of the vagina

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

• Pericarditis, pericardial effusion, and tamponade
• Megaloblastic anemia
• Mood changes
• Paralysis
• Effects on speech, including dysarthria and aphasia
• Myelopathy
• Visual disturbances, blurred vision
• Thrombosis (brain, deep vein thrombosis, and retinal vein thrombosis)
• Low blood pressure
• Diabetes
• Pharyngitis, apnea, asthma, gingivitis
• Small intestine inflammation
• Blood in stool
• Malabsorption
• Acne, skin wounds, nail pigmentation changes, bruising
• Fractures
• Kidney failure, oliguria, azotemia, and anuria
• Increased uric acid levels
• Increased creatinine and urea levels in serum
• Liver damage
• Abnormal breast development

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

• Infections, sepsis, opportunistic infections
• Severe bone marrow failure, anemia caused by the bone marrow's inability to produce blood cells (aplastic anemia), lymphadenopathy, lymphoproliferative disorders (overproduction of white blood cells), eosinophilia, neutropenia, and hypogammaglobulinemia
• Immunosuppression
• Insomnia
• Disorders of intellectual function, such as thinking, memory, and logical reasoning
• Joint pain and/or muscle pain, lack of strength
• Muscle weakness (myasthenia)
• Meningeal reaction (paralysis, vomiting), acute aseptic meningitis
• Sensory disturbances, changes in taste (metallic taste)
• Conjunctivitis, retinopathy, vision loss, puffy eyes
• Blepharitis, tearing, and photophobia
• Tumor lysis syndrome
• Allergic vasculitis, sweat gland inflammation
• Respiratory disorders, shortness of breath, pneumonia
• Pulmonary infections
• Pleural effusion
• Toxic dilation of the colon (toxic megacolon), blood in vomit
• Reactivation of chronic hepatitis, acute liver degeneration, viral hepatitis, liver failure
• Painful swelling of the skin around the nails
• Expansion of small blood vessels in the skin
• Proteinuria
• Loss of libido, impotence
• Menstrual disorders
• Vaginal discharge
• Infertility
• Fever, impaired wound healing

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

• Bleeding, hemorrhage
• Psychosis
• Fluid accumulation in the brain and lungs
• Metabolic disorder
• Necrosis of the skin, exfoliative dermatitis
• Jawbone damage (due to overproduction of white blood cells)
• Redness and peeling of the skin

Methotrexate must not be administered intrathecally, as it may cause very severe side effects.

Reporting side effects

If you experience any side effects, including any possible side effects not listed in this leaflet, tell your doctor or pharmacist. Side effects can be reported directly to the Department of Adverse Reaction Monitoring of Medicinal Products, Medical Devices, and Biocides of the Office for Registration of Medicinal Products, Medical Devices, and Biocides
Al. Jerozolimskie 181C
02-222 Warsaw
tel.: +48 22 49 21 301
fax: +48 22 49 21 309
website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Metotreksat Accord

Store the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the label/carton after EXP.
The expiry date refers to the last day of that month.
Do not store above 30°C.
Vial after first opening – use immediately after opening.
After dilution
Chemical and physical stability of the diluted solution has been demonstrated in glucose (5%) and sodium chloride (0.9%) solutions at concentrations of 5 mg/ml and 20 mg/ml for 36 hours at 20-25°C and 35 days at 2-8°C. The diluted product is stable in both diluents, 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 storage conditions and storage time before use are the responsibility of the user, but no longer than 24 hours at 2-8°C, unless dilution was performed under controlled, validated aseptic conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the packaging and other information

What Metotreksat Accord contains

• The active substance is methotrexate.
• 1 ml of solution contains 100 mg of methotrexate. The other ingredients are sodium hydroxide and water for injections.

What Metotreksat Accord looks like and contents of the pack

The medicine is a clear, yellow solution.
Pack sizes:
1 vial of 5 ml, 10 ml, or 50 ml in a cardboard box.
5 vials of 5 ml, 10 ml, or 50 ml in a cardboard box.
Not all pack sizes may be marketed.

Marketing authorization holder

Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warsaw
Tel: 22 577 28 00

Manufacturer/Importer

Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice
Accord Healthcare B.V.
Winthontlaan 200
3526 KV Utrecht
Netherlands

This medicine is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Date of last revision of the leaflet: January 2025

The following information is intended for healthcare professionals only.

WARNINGS

If methotrexate is used to treat cancer, the dose must be carefully
adjustedbased on body surface area. Fatal cases of poisoning have been reported after incorrectly calculateddoses were administered.

Instructions for preparation, handling, and disposal of Metotreksat Accord 100 mg/ml, concentrate for solution for infusion

Before use, inspect the solution. Only use a clear solution without any particles.
The methotrexate infusion solution can then be diluted in a suitable diluent, free of preservatives, such as glucose (5%) or sodium chloride (0.9%) solution. The chemical and physical stability of the diluted solution has been demonstrated in glucose (5%) and sodium chloride (0.9%) solutions at concentrations of 5 mg/ml and 20 mg/ml for 36 hours at 20-25°C and 35 days at 2-8°C. The diluted product is stable in both diluents, 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 storage conditions and storage time before use are the responsibility of the user, but no longer than 24 hours at 2-8°C, unless dilution was performed under controlled, validated aseptic conditions.
When handling the product, the following general guidelines should be considered: the product should be used and administered only by trained personnel; mixing the solution should be done in designated areas, ensuring protection of personnel and the environment (e.g., safety cabinets); protective clothing (including gloves, safety glasses, and masks, if necessary) should be worn.
Pregnant women, who are part of the medical staff, should not handle and/or administer Metotreksat Accord.
Methotrexate should not come into contact with skin or mucous membranes. In case of contamination, the affected area should be rinsed immediately with a large amount of water for at least ten minutes.
The product is for single use only. Unused solution should be discarded. Waste should be disposed of in appropriate, separate containers, clearly labeled regarding their contents (as significant amounts of anticancer agents may be present in the patient's bodily fluids and excreta, it is recommended that these, as well as materials such as contaminated bedding, be treated as hazardous waste). Any remaining unused product or waste should be disposed of in accordance with local regulations by incineration.
In case of accidental contamination due to spillage, appropriate procedures should be followed; exposure of workers to anticancer agents should be recorded and monitored.