Patient leaflet - Methotrexate 25 mg / ml solution for injection

1. What Methotrexate 25 mg/ml is and what it is used for

Methotrexate 25 mg/ml contains the active substance methotrexate. Methotrexate is a cytostatic that inhibits cell growth. Methotrexate has its greatest effect on cells which increase frequently like cancer cells, bone marrow cells and skin cells.

Methotrexate 25 mg/ml is used in the treatment of the following types of cancer:

acute lymphocytic leukaemia,
prophylaxis of meningeal leukaemia,
non-Hodgkin’s lymphomas,
osteogenic sarcoma,
adjuvant and in advance disease of breast cancer,
metastatic or recurrent head and neck cancer,
choriocarcinoma and similar trophoblastic diseases,
advanced cancer of urinary bladder.

2. What you need to know before you use Methotrexate 25 mg/ml

Do not use Methotrexate 25 mg/ml

If you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6).
If you have significant liver disease (Your doctor decides the severity of your disease).
If you have significant kidney disease (Your doctor decides the severity of your disease)
If you have disorders of the blood-forming system.
If you have severe or existing infection such as tuberculosis and HIV.
If you have ulcers in the mouth and throat or ulcers in the stomach and gut.
If you are breastfeeding (see section Pregnancy, breast-feeding and fertility).
If you have increased alcohol consumption.

You should not be given live vaccines during treatment with Methotrexate 25 mg/ml.

Tell your doctor before you use Methotrexate 25 mg/ml if you think any of the above apply to you.

Warnings and precautions

Methotrexate can cause serious and sometimes life-threatening undesirable effects. Your doctor will talk to you about the advantages and risks of the treatment and what the early signs and symptoms of undesirable effects are.
Methotrexate may cause decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting, thereby increasing chances of you getting the infections (e.g. pneumonia) or increased bleedings.
Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. If you experience symptoms of spitting or coughing up blood, you should contact your doctor immediately.
Methotrexate temporarily affects sperm and egg production. Since treatment with methotrexate may lead to infertility, it might be advisable for male patients to look into the possibility of sperm preservation before starting treatment. Methotrexate can cause miscarriage and severe birth defects. You should avoid having a baby if you are being given methotrexate at the time and for at least 6 months after the end of your treatment with methotrexate if you are a woman. If you are a man you should avoid fathering a child if you are being given methotrexate at the time and for at least 3 months after the end of your treatment. See also section “Pregnancy, breast-feeding and fertility”.
Methotrexate may make your skin more sensitive to sunlight. Avoid intense sun and do not use sun-beds or a sun-lamp without medical advice. To protect your skin from intense sun, wear adequate clothing or use a sunscreen with a high protection factor.

Talk to your doctor, pharmacist or nurse before taking Methotrexate 25 mg/ml

If you are to undergo radiotherapy at the same time as the Methotrexate treatment. The risk of tissue and bone damage can increase with simultaneous treatment.
- If you are having treatment in your spine (intrathecally) or in a vein (intravenously) this can cause a potentially life-threatening inflammation in the brain.
- If you have symptoms connected to a medical condition that means that fluid is retained in your body, for example in the lungs or in the abdomen.
- If you have impaired kidney function.
- If you have impaired liver function.
- If you have an infection.
- If you need to be vaccinated. Methotrexate can reduce the effect of the vaccines.
- If you have insulin dependent diabetes, methotrexate treatment should be carefully monitored.

If you, your partner or your caregiver notice new onset or worsening of neurological symptoms including general muscle weakness, disturbance of vision, changes in thinking, memory and orientation leading to confusion and personality changes contact your doctor immediately because these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

Recommended follow-up examinations and precautions:

Even when methotrexate is used at low doses, serious side effects can occur. In order to recognise these in good time, your doctor must carry out check-ups and laboratory tests.

Before the start of treatment:

Before treatment is started your doctor may carry out blood tests, and also to check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests.

Other medicines and Methotrexate 25 mg/ml

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, Methotrexate affects or is affected by certain other medicinal products against:

Pain and inflammation (so called NSAIDs and salicylates)
Cancer (cisplatin, cytarabine, mercaptopurine, fluorouracil)
Infections (antibiotics such as penicillins, tetracycline, ciprofloxacin and chloramphenicol)
Asthma (theophylline)
Vitamin preparations containing folic acid or substances like folic acid
Rheumatism (leflunomide)
High blood pressure (furosemide)
Gout (probenicide)
Radiotherapy
Stomach ulcers, heartburn, reflux (such as omeprazole, pantoprazole, lanzoprazole
Epilepsy (phenytoin)
Nitrous oxide (‘laughing gas’ that is inhaled to give pain relief).
Psoriasis or severe acne (retinoids, such as acitretin or isotretinoin)
Rheumatoid arthritis or bowel disease (sulphsalazine)
Rejection after an organ transplant (azathioprine)
If you need to be vaccinated with a live vaccination
barbiturates (a group of medicines used as hypnotics, sedatives, anaesthetics or as anticonvulsants)
tranquillisers
hypoglycaemic drugs (used to treat diabetes)
pyrimethamine (used to prevent and treat malaria)
oral contraceptives
Metamizole (synonyms novaminsulfon and dipyrone) (medicine against severe pain and /or fever).

Methotrexate 25 mg/ml with food, drink and alcohol

During treatment with Methotrexate 25 mg/ml, you should not drink any alcohol and you should avoid excessive consumption of coffee, soft drinks containing caffeine and black tea. Also make sure you drink plenty of liquids during treatment with Methotrexate 25 mg/ml because dehydartion (reduction in body water) can increase the toxicity of Methotrexate 25 mg/ml.

Pregnancy, breast-feeding and fertility

Pregnancy

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Do not use Methotrexate 25 mg/ml during pregnancy except if your doctor has prescribed it for oncology treatment. Methotrexate can cause birth defects, harm the unborn child or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. It is therefore very important that methotrexate is not given to pregnant women or to women who are planning to become pregnant unless used for oncology treatment.

For non-oncological indications, in women of child-bearing age the possibility of a pregnancy must be ruled out, e.g. by pregnancy tests, before treatment is started.

Do not use Methotrexate 25 mg/ml if you are trying to become pregnant. You must avoid becoming pregnant during treatment with methotrexate and for at least 6 months after the end of treatment. Therefore, you must ensure that you are taking effective contraception for the whole of this period (see also section "Warnings and precautions").

If you become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. If you do become pregnant during treatment, you should be offered advice regarding the risk of harmful effects on the child through treatment.

If you want to become pregnant, you should speak with your doctor, who may refer you for specialist advice before the planned start of treatment.

Male fertility

The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded and there is no information regarding higher methotrexate doses. Methotrexate can have a genotoxic effect. This means that the medicine can cause genetic mutations. Methotrexate can affect the production of sperm, which is associated with the possibility of birth defects.

You should avoid fathering a child or to donate semen during treatment with methotrexate and for at least 3 months after the end of treatment. As treatment with methotrexate at higher doses commonly used in cancer treatment can cause infertility and genetic mutations, it may be advisable for male patients treated with methotrexate doses higher than 30 mg/week to consider sperm preservation before the beginning of treatment (see also section "Warnings and precautions").

Breast-feeding

Methotrexate is excreted in breast milk in such quantities that there are risks of affecting the baby. Breast-feeding should therefore be suspended prior to treatment with Methotrexate.

Driving and using machines

Undesirable effects such as tiredness and dizziness may occur. If you feel tired or dizzy do not drive and do not use machines.

Sodium

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

3. How to use Methotrexate 25 mg/ml

Methotrexate 25 mg/ml is given to you by healthcare professionals.

The dose you receive and how often you receive the dose, depend on the disease you are being treated for your state of health and your age, weight and body surface. Methotrexate 25 mg/ml can be given in a muscle (intramuscularly), in a vein (intravenously), in an artery (intra-arterially) or in the spine (intrathecally).

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with plenty of water.

Your doctor may instruct you to take sodium bicarbonate or acetazolamide tablets while receiving your medicine to help make sure that methotrexate is not concentrated in the kidneys. If you receive methotrexate in high doses, you will receive calcium folinate as well to lessen the side effects of methotrexate.

If you use more Methotrexate 25 mg/ml than you should

Your doctor decides on the dosage, which is given by healthcare staff. Overdose is therefore unlikely. An overdose of methotrexate can lead to severe toxic reactions. Overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, vomiting blood or black or bloody stools. The antidote in case of an overdose is calcium folinate.

If you forget or stop using Methotrexate 25 mg/ml

You should not interrupt or discontinue Methotrexate 25 mg/ml treatment, unless you have discussed this with your doctor. In case you forget your appointment for the next dose, contact your doctor as soon as possible to schedule a new appointment. If you suspect severe 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 side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Methotrexate 25 mg/ml can have undesirable effects which may be dangerous or life-threatening. During the treatment you should be alert to signs of undesirable effects and report them to your doctor.

Contact a doctor immediately if you notice any of the following undesirable effects. You may need immediate medical care.

Unexplained breathlessness, dry cough or wheezing (symptoms of lung problems).
Sudden itching, skin rash (urticaria), swollen hands, feet, ankles, face, lips, mouth or throat (which can make it hard to breathe and swallow). It can also feel as if you are going to faint (symptoms of a severe allergic reaction).
Vomiting, diarrhoea or stomatitis and peptic ulcers (Symptoms of effect on gastrointestinal track).
Yellowing of the skin or eyes, dark-coloured urine (symptoms of effect on the liver).
Fever, shivering, aching body and sore throat (symptoms of infection).
Unexpected bleeding (for example bleeding gums, dark urine, blood in the urine or vomit) or unexpected bruising, black, tar-like faeces – this can be due to a reduced coagulation capacity or bleeding from the stomach or gut).
Skin rashes with flaking or blistering and effects on mucous membranes e.g. in the nose (symptoms of Stevens-Johnsons syndrome, toxic epidermal necrolysis and erythema multiforme).
Abnormal behaviour, transient blindness and generalised seizures (Symptoms of effect on central nervous system).
Paralysis (paresis).

The following information is intended for medical or healthcare professionals only

WARNINGS

The dose must be adjusted carefully depending on the body surface area if methotrexate is used for the treatment of tumour diseases. Fatal cases of intoxication have been reported after administration of incorrectly calculated doses.

Instruction on how to prepare, handle and dispose of Methotrexate 25 mg/ml solution for injection

The solution should be visually inspected prior to use. Only clear solution practically free from particles should be used.

Methotrexate injection may be further diluted with an appropriate preservative-free medium such as glucose solution (5%) or sodium chloride solution (0.9%).

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

Pregnant healthcare personnel should not handle and/or administer Methotrexate.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be irrigated immediately with copious quantities of water for at least ten minutes.

For single use only. Any unused solution should be discarded. Waste should be disposed of carefully in suitable separate containers, clearly labelled as to their contents (as the patient's body fluids and excreta may also contain appreciable amounts of antineoplastic agents and it has been suggested that they, and material such as bed linen contaminated with them, should also be treated as hazardous waste). Any unused product or waste should be disposed of in accordance with local requirements by incineration.

(6034585) : Date : 15_04_2025, (R) 08.07.2025, 10.07.2025

		-
	Customer	Accord
	Description	Methotrexate 25 mg
	Market	UK
	Language	English
		450 x 450 mm (PIL) FF- 80 x 45 mm
		9
	Version No.	2 (Page 2 of 2) (IA/040/G)
	Date	27.05.22 (Methotrexate 25mg (ACC-UK)PIL)

Adequate procedures should be in place for accidental contamination due to spillage; staff exposure to antineoplastic agents should be recorded and monitored.

10 5981 3 6034585

(6034585) : Date : 15_04_2025, (R) 08.07.2025, 10.07.2025

A list of undesirable effects that have been reported in treatment with Methotrexate is set out below according to how common they are. Very common (may affect more than 1 in 10 people):

Loss of appetite, nausea, vomiting, abdominal pain, impaired digestion, dyspepsia
Inflammation and ulceration in mouth and throat
Increase in level of liver enzyme

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

Herpes zoster
Effects on the blood e.g. anaemia, leukocytopenia, thrombocytopenia
Headache, Tiredness, drowsiness
Dry cough, shortness of breath, chest pain, fever
Diarrhoea
Rashes, redness and itching

Uncommon (may affect up to 1 in 100 people)

Pancytopenia, agranulocytosis
Inflammation of blood vessels
Anaphylactoid reactions and allergic vasculitis
Vertigo, confusion, depression
Convulsions, encephalopathy
Lymphoma (tumour in lymph tissue)
Pulmonary fibrosis
Bleeds and ulcers in the stomach and intestinal tract
Inflammation of pancreas
Liver fibrosis and cirrhosis, fatty liver
Diabetic complications
Reduced levels of albumin
Sunburn-like reactions due to increased sensitivity of the skin to sunlight
Urticaria
Enhanced pigmentation of the skin
Hair loss, herpes zoster, painful lesions of scaly patches caused by psoriasis
Increase of rheumatic nodules (lumps of tissues)
Effects on skin and mucous membrane, sometimes serious (Stevens-Johnsons syndrome, toxic epidermal necrolysis)
Inflammation and ulceration of urinary bladder, haematuria, dysuria
Inflammation and ulceration of vagina
Brittle bones (osteoporosis), arthralgia, myalgia

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

Pericarditis, pericarditis effusion and tamponade
Megaloblastic anaemia
Mood swings
Paresis
Effects on speech including dysarthria and aphasia
Myelopathy
Visual disturbance, blurred vision
Thrombosis (cerebral, deep vein and retinal vein)
Low blood pressure
Pharyngitis apnoea, bronchial asthma
Gingivitis
Inflammation in the small intestine
Blood in the faeces
Malabsorption
Liver damage
Acne, sores on the skin, pigment changes of the nails, bruises
Fractures
Renal failure, oliguria, azotaemia and anuria
Hyperuricemia
Elevated serum creatinine and urea level
Abnormal development of mammary glands
Raised blood sugar levels (diabetes mellitus)

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

Infections, sepsis opportunistic infections
Severe failure of the bone marrow, anaemia due to the fact that the bone marrow cannot produce blood cells (aplastic anaemia), Lymphadenopathy, lymphoproliferative disorder (excessive growth of white blood cells), eosinophilia and neutropenia.
Immunosuppression
Hypogammaglobulinaemia
Insomnia
impaired intellectual functions such as thinking, remembering and reasoning
Joint and/or muscle pain, lack of strength
Myasthenia (muscle weakness)
Abnormal sensations, changes in sense of taste (metallic taste)
Meningism (Paralysis, vomiting), acute aseptic meningitis
Conjunctivitis, retinopathy, loss of vision, puffy eye
Inflammation eye follicles epiphora and photophobia
Tumour lysis syndrome
Problem with lung function, shortness of breath, pneumonia
Infections of lungs
Pleural effusion
Dilation of colon (Toxic megacolon)
Reactivation of chronic hepatitis, acute liver degeneration, herpes simplex hepatitis, liver insufficiency
Painful swelling of skin around nail
Expansion of small blood vessels in the skin (paronychia)
Allergic vasculitis, hidradentis
Proteinuria
Loss of libido impotence
Menstrual disorder
Discharge from the vagina
Infertility
Fever, impaired wound healing
Not known (frequency cannot be estimated from the available data):
- Bleeding, blood outside of vessels
- Psychosis
- Accumulation of fluid in brain and lungs
- Metabolic disorder
- Skin necrosis, exfoliative dermatitis
- Bone damage in the jaw (secondary to excessive growth of white blood cells)
- Redness and shedding of skin

If you receive Methotrexate 25 mg/ml in the spine the following undesirable effects are common (may affect up to 1 in 100 people):

Headache
Fever
Inflammation in the so-called arachnoid membrane in the brain and spinal cord which can cause backache, stiffness in the neck, vomiting, fever and impaired general state of health this can occur within a couple of hours after you have received the Methotrexate injection but usually disappears within a few days
Hemiplegia or total paralysis, weakness in one or all extremities and cramp attacks (usually occurring after repeated Methotrexate injected into the spinal cord)
Effect on the nervous system which may start with confusion, irritation and tiredness. This gets worse over time and leads to dementia (increasing loss of memory, disorientation and confusion), speech difficulties, coordination and balance difficulties, increased muscle stiffness, cramps and coma. This state can occur several months or years after the start of treatment with Methotrexate injected into the spinal cord. The condition can be life-threatening; it chiefly occurs if you have large quantities of Methotrexate injected into the spinal cord in combination with radiotherapy to the head and/or Methotrexate in some other form.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Methotrexate 25 mg/ml

Keep this medicines out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label/carton after EXP. The expiry date refers to the last day of the month.

Store below 25°C.

Vial after first opening – Use immediately after opening.

After dilution – 24 hours

Chemical and physical stability of the diluted solution have been demonstrated for 24 hours. For microbial point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and condition prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution/ reconstitution has taken place in controlled and validated aseptic conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines no longer required. These measures will help to protect the environment.

6. Contents of the pack and other information

What Methotrexate 25 mg/ml contains

The active substance is methotrexate. 1 ml solution contains 25 mg methotrexate.
The other ingredients are sodium chloride, sodium hydroxide/hydrochloric acid (to adjust the pH) and water for injection.

What Methotrexate 25 mg/ml looks like and contents of the pack

The medicinal product is a clear yellow solution.

Package size: 1 vial in carton for 2 ml, 20 ml and 40 ml pack size 10 vials per packs for 20 ml and 40 ml

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare Limited

Sage House,

319, Pinner Road

North Harrow

Middlesex HA1 4HF

United Kingdom

Manufacturer