Methotrexate accord

Package leaflet: Information for the user

Metotreksat Accord, 100 mg/ml, concentrate for solution for infusion
Methotrexatum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm other people, even if their symptoms are the same.
• If any adverse reactions occur, including any possible adverse reactions not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

1. What Metotreksat Accord is and what it is 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 package and other information

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

The active substance in Metotreksat Accord is methotrexate. Methotrexate is a cytostatic agent
which inhibits cell growth. Methotrexate has the greatest effect on rapidly dividing cells, such as
tumour cells, bone marrow cells, and skin cells.
Metotreksat Accord is used in the treatment of the following types of tumours:

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

2. Important information before using Metotreksat Accord

When not to use Metotreksat 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 disorders of the blood-forming system,
• if the patient has a severe infection, such as tuberculosis or HIV,
• if the patient has oral or pharyngeal ulcers or peptic ulcer disease,
• if the patient is breastfeeding (see section: Pregnancy, breastfeeding and fertility).

Live vaccines should not be administered during treatment with Metotreksat Accord.
Please inform your doctor if any of the above conditions apply to you before using this medicine.
Warnings and precautions

• Methotrexate may cause serious, sometimes life-threatening, adverse effects. Your doctor will discuss with you the benefits and risks of treatment, as well as early signs of adverse reactions.
• Methotrexate may reduce the number of cells responsible for immunity, oxygen transport, and blood clotting, increasing the risk of infections (e.g. pneumonia) or excessive bleeding.
• Cases of acute pulmonary haemorrhage have been reported in patients with underlying rheumatological disease during methotrexate treatment. If the patient develops symptoms such as coughing up blood or haemoptysis, immediate medical attention is required.
• Methotrexate temporarily impairs the production of sperm and egg cells. Methotrexate treatment may lead to infertility; therefore, male patients should consider sperm cryopreservation before starting treatment. Methotrexate may cause miscarriage and severe congenital malformations. Female patients should avoid becoming pregnant during methotrexate therapy and for at least 6 months after treatment ends. Male patients should avoid impregnating their partner during methotrexate therapy and for at least 3 months after treatment ends. See also section “Pregnancy, breastfeeding and fertility”.
• Methotrexate may increase skin sensitivity to sunlight. Exposure to intense sunlight should be avoided, and use of sunbeds or tanning lamps is not recommended without prior consultation with a doctor. To protect the skin from intense sunlight, wear appropriate clothing or apply a high-protection sunscreen.

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

• if the patient is undergoing radiotherapy at the same time as methotrexate treatment. Concurrent therapy may increase the risk of tissue and bone damage,
• if the patient is receiving intrathecal or intravenous therapy, which may cause potentially life-threatening encephalitis. Metotreksat Accord 100 mg/ml must not be administered intrathecally.
• if the patient has fluid retention disorders, for example in the lungs or abdomen,
• if the patient has impaired kidney function,
• if the patient has impaired liver function,
• if the patient has an infection,
• if the patient needs to receive a vaccine. Methotrexate may reduce vaccine effectiveness,
• 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 generalised muscle weakness, vision disturbances, changes in thinking, memory, and orientation
leading to disorientation and personality changes, contact the doctor immediately, as these may be signs
of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).
Recommended monitoring tests and precautions during treatment:
Even when methotrexate is used at low doses, severe adverse effects may occur. To detect them early,
your doctor must perform regular check-ups and laboratory tests.
Before starting treatment:
Prior to initiating therapy, your doctor may perform blood tests and assess kidney and liver function.
A chest X-ray may also be performed. Additional tests may be carried out during and after treatment.
Do not miss scheduled blood test appointments.
Metotreksat Accord and other medicines
Tell your doctor or pharmacist about all medicines currently or recently taken, including those planned
for future use. Methotrexate interacts with or is affected by certain other medicinal products used in the
treatment of:

• 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 folic acid-like substances,
• rheumatism (leflunomide),
• high blood pressure (furosemide),
• gout (probenecid),
• radiotherapy,
• peptic ulcer disease, heartburn, reflux (omeprazole, pantoprazole, lansoprazole),
• epilepsy (phenytoin),
• psoriasis or severe acne (retinoids such as acitretin or isotretinoin),
• rheumatoid arthritis or inflammatory bowel disease (sulfasalazine),
• organ transplant rejection (azathioprine),
• if the patient needs to receive a live vaccine,
• nitrous oxide (“laughing gas”) inhaled for pain relief,
• barbiturates (a group of drugs used as sedatives, hypnotics, anaesthetics, or anticonvulsants),
• sedatives,
• hypoglycaemic agents (used in diabetes treatment),
• pyrimethamine (used for prevention and treatment of malaria),
• oral contraceptives,
• metamizole (synonyms: novaminsulfone and dipyrone) (a strong analgesic and/or antipyretic).

Metotreksat Accord with food, drink, and alcohol
During treatment with Metotreksat Accord, alcohol consumption should be avoided, as well as excessive
intake of coffee, caffeinated soft drinks, and black tea. Patients should also drink large amounts of fluids
during treatment, since dehydration (reduced body water) 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 become pregnant,
she should consult her doctor before using this medicine.
Do not use Metotreksat Accord during pregnancy unless prescribed by a doctor for oncological indications.
Methotrexate may cause congenital malformations, harm the unborn child, or lead to miscarriage. This is
associated with developmental abnormalities of the skull, face, heart and blood vessels, brain, and limbs.
Therefore, it is extremely important that female patients who are pregnant or planning pregnancy do not
take methotrexate, except for oncological indications.
If the patient is of reproductive age, pregnancy must be ruled out before starting non-oncological treatment,
e.g. by performing a pregnancy test.
Do not use Metotreksat Accord if the patient is pregnant or trying to become pregnant.
The patient must absolutely avoid becoming pregnant during methotrexate treatment and for at least
6 months after treatment ends. Effective contraception must be used throughout this period (see also
section “Warnings and precautions”).
If the patient becomes pregnant during treatment or suspects she may be pregnant, she should contact
her doctor immediately. If pregnancy occurs during treatment, advice should be sought regarding the
possible harmful effects of treatment on the foetus.
If the patient plans to become pregnant, she should consult her treating physician, who may refer her
to a specialist for pre-treatment counselling.
Male fertility
Available evidence does not indicate an increased risk of developmental abnormalities or miscarriages
following paternal exposure to methotrexate at doses below 30 mg/week. However, a risk cannot be
entirely ruled out, and there is no information available for higher methotrexate doses. Methotrexate
may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm production,
potentially leading to congenital abnormalities.
The patient should avoid impregnating his partner and donating sperm during methotrexate treatment
and for at least 3 months after treatment ends. Given that treatment with higher methotrexate doses
typically used in cancer therapy may cause infertility and genetic mutations, sperm banking before
treatment initiation may be recommended for men receiving methotrexate doses above 30 mg/week
(see also section “Warnings and precautions”).
Breastfeeding
Methotrexate passes into human milk in amounts that pose a risk to the infant. Breastfeeding must be
discontinued before starting methotrexate treatment.
Driving and operating machinery
Adverse effects such as fatigue or dizziness may occur. If the patient experiences fatigue or dizziness,
driving and operating machinery should be avoided.
Metotreksat Accord contains sodium
This medicine contains 194 mg of sodium (main component of table salt) in the maximum recommended
daily dose. This corresponds to 9.7% of the recommended maximum daily dietary sodium intake for adults.

3. How to use Metotreksat Accord

Metotreksat Accord is administered by trained medical personnel.
The dose and frequency of administration depend on the disease being treated, the patient's health status, age, body weight, and body surface area. Metotreksat Accord may be administered intramuscularly, intravenously, or intra-arterially.
Metotreksat Accord must not be administered intrathecally (into the spinal canal).
Higher doses are usually given as a 24-hour infusion, either alone or in combination with other anticancer drugs.
Metotreksat should not come into contact with skin or mucous membranes. In case of contamination, the affected area should be immediately rinsed with large amounts of water.
The physician may recommend taking sodium bicarbonate tablets or acetazolamide during treatment with this medicine to ensure that methotrexate does not accumulate in the kidneys. If the patient receives high-dose methotrexate, calcium folinate will also be administered to reduce methotrexate's adverse effects.
Use of a higher than recommended dose of Metotreksat Accord
The physician determines the dosage, which is administered by medical personnel. Therefore, overdose is unlikely. However, methotrexate overdose may lead to severe toxic reactions.
Symptoms of overdose may include easy bruising or bleeding, unusual weakness, oral 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 otherwise agreed with your doctor.
If an appointment for the next dose is missed, contact your doctor as soon as possible to reschedule the next visit. In case of suspected severe adverse reactions, contact your doctor immediately for advice.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Metotreksat Accord may cause serious or life-threatening adverse reactions.
During treatment, be alert for adverse reactions and report them to your doctor.
Contact your doctor immediately if any of the following adverse symptoms occur. The patient may require immediate medical attention.

• Unexplained shortness of breath, dry cough, or wheezing (symptoms of lung disorders).
• Sudden itching, rash (urticaria), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may make breathing or swallowing difficult). The patient may also feel faint (symptoms of a severe allergic reaction).
• Vomiting, diarrhoea, inflammation of the mouth, and ulcerative 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. bleeding gums, dark urine, blood in urine or vomit) or petechiae, black tarry stools – this may result from impaired blood clotting or bleeding within the stomach or intestines.
• Skin rashes with peeling skin or blisters, effects on mucous membranes, e.g. in the nasal cavity (symptoms of Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme).
• Behavioral disturbances, transient blindness, and generalized seizures (symptoms of central nervous system effects).
• Paralysis (paresis)

Below is a list of adverse reactions reported during methotrexate treatment, categorized by frequency of occurrence.
Very common (may affect more than 1 in 10 people):

• Loss of appetite, nausea, vomiting, abdominal pain, digestive disturbances, dyspepsia
• Inflammation and ulceration of the mouth and throat
• Increased liver enzyme activity

Common (may affect up to 1 in 10 people):

• Herpes zoster
• Effects on blood, e.g. anaemia, leukopenia, thrombocytopenia
• Diarrhoea
• 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
• Anaphylactoid reactions and allergic vasculitis
• Dizziness, disorientation, depression
• Seizures, encephalopathy
• Lymphoma (lymph tissue tumour)
• Pulmonary fibrosis
• Bleeding and ulceration in the stomach and intestines
• Pancreatitis
• Diabetic complications
• Decreased albumin concentration
• Increased skin pigmentation
• Hair loss, painful peeling lesions caused by psoriasis
• Increase in rheumatoid nodules (nodules in tissues)
• Effects on skin and mucous membranes, sometimes severe (Stevens-Johnson syndrome, toxic epidermal necrolysis)
• Sunburn-like reactions due to increased skin sensitivity to sunlight
• Urticaria
• Bone fragility (osteoporosis), joint pain, muscle pain
• Fibrosis and cirrhosis of the liver, fatty liver
• Inflammation and ulceration of the urinary bladder, haematuria, difficulty urinating
• Inflammation and ulceration of the vagina

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

• Pericarditis, pericardial effusion, and cardiac tamponade
• Megaloblastic anaemia
• Mood swings
• Paresis
• Speech disorders, including dysarthria and aphasia
• Myelopathy
• Visual disturbances, blurred vision
• Thrombosis (in the brain, deep vein thrombosis, retinal vein thrombosis)
• Low blood pressure
• Diabetes
• Sore throat, apnoea, bronchial asthma, gingivitis
• Inflammation of the small intestine
• Blood in stool
• Malabsorption
• Acne, skin lesions, nail pigmentation changes, bruising
• Fractures
• Renal failure, oliguria, azotemia, and anuria
• Increased uric acid levels
• Increased serum creatinine and urea levels
• Liver damage
• Abnormal breast gland development

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

• Infections, sepsis, opportunistic infections
• Severe bone marrow failure, anaemia due to the bone marrow's inability to produce blood cells (aplastic anaemia), enlarged lymph nodes, lymphoproliferative disorders (overproduction of white blood cells), eosinophilia, neutropenia, and hypogammaglobulinaemia
• Immunosuppression
• Insomnia
• Cognitive disturbances, such as thinking, memory, and logical reasoning
• Joint and (or) muscle pain, weakness
• Myasthenia (muscle weakness)
• Meningeal reaction (paralysis, vomiting), acute aseptic meningitis
• Sensory disturbances, taste alterations (metallic taste)
• Conjunctivitis, retinopathy, vision loss, puffy eyes
• Blepharitis, lacrimation, photophobia
• Tumour lysis syndrome
• Allergic vasculitis, sweat gland inflammation
• Pulmonary function disorders, shortness of breath, pneumonia
• Lung infections
• Pleural effusion
• Colonic dilation (toxic megacolon), blood in vomit
• Reactivation of chronic hepatitis, acute liver degeneration, herpes virus-induced hepatitis, liver failure
• Painful swelling of the skin around the nails
• Telangiectasia (dilation 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, haemorrhage
• Psychosis
• Fluid accumulation in the brain and lungs
• Metabolic disorder
• Skin necrosis, exfoliative dermatitis
• Jaw bone damage (due to overproduction of white blood cells)
• Redness and peeling of the skin

Metotreksat Accord must not be administered intrathecally, as this may result in very severe adverse reactions.
Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Metotreksat Accord

Keep this 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 the stated month.
Do not store above 30°C.
Vial after first opening – Use immediately after opening.

After dilution
Chemical and physical in-use stability has been demonstrated for the diluted solution 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 for 35 days at 2–8°C. The diluted product is stable in both diluents at 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 user is responsible for the conditions and duration
of storage prior to use, which should not exceed 24 hours at 2–8°C, unless dilution has been carried out
under controlled and validated aseptic conditions.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack 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 Authorisation 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 single member S.A.
64th Km National Road Athens, Lamia
Schimatari, 32009
Greece
This medicinal product is authorised in the Member States of the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

The following information is intended for healthcare professionals only.
WARNINGS
If methotrexate is used in the treatment of malignant diseases, the dose must be carefully
adjusted according to body surface area. Fatal cases of poisoning have been reported following
incorrectly calculated doses.
Instructions for preparation, handling and disposal of Metotreksat Accord 100 mg/ml,
concentrate for solution for infusion
Inspect the solution before use. Only a clear, particle-free solution should be used.
The methotrexate solution for infusion may subsequently be diluted in a suitable, preservative-free
diluent such as glucose (5%) or sodium chloride (0.9%) solution. Chemical and physical stability of
the diluted solution has been demonstrated in 5% glucose and 0.9% sodium chloride solutions at
concentrations of 5 mg/ml and 20 mg/ml for 36 hours at 20–25°C and for 35 days at 2–8°C. The
diluted product is stable in both diluents at both concentrations for 36 hours at 20–25°C and for 35
days at 2–8°C. From a microbiological standpoint, the product should be used immediately. If the
product is not used immediately, the user is responsible for the storage conditions and duration
prior to use, not exceeding 24 hours at 2 to 8°C, unless dilution was performed under controlled and
validated aseptic conditions.
The following general recommendations should be observed when handling this product: the
product should be handled and administered only by trained personnel; mixing should be carried
out in designated areas with appropriate protection of personnel and environment (e.g., safety
cabinets); protective clothing (including gloves, protective goggles, and masks if necessary) must
be worn.
Pregnant healthcare personnel must not handle or (and) administer Metotreksat Accord.
Methotrexate must not come into contact with skin or mucous membranes. In case of contamination,
the affected area must be immediately washed with large amounts of water for at least ten minutes.
The product is for single use only. Any unused solution must be discarded. Waste must be disposed
of in appropriate, separate containers clearly labeled with their contents (since body fluids and
excreta of patients may contain significant amounts of cytotoxic agents, both these fluids and
materials such as contaminated bed linen should also be treated as hazardous waste). All unused
product and waste material must be disposed of in accordance with local regulations by incineration.
In case of accidental spillage, appropriate procedures must be followed; exposure of personnel to
cytotoxic agents should be recorded and monitored.