Methotrexate 2.5 mg Tablets

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

1. What Methotrexate 2.5 mg Tablets are and what they are used for
2. What you need to know before you take Methotrexate 2.5 mg Tablets
3. How to take Methotrexate 2.5 mg Tablets
4. Possible side effects
5. How to store Methotrexate 2.5 mg Tablets
6. Contents of the pack and other information

• if you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6)
• if you are breast-feeding and additionally, for non-oncologic indications (for non-cancer treatment)
• if you are pregnant (see section: Pregnancy, breast-feeding and fertility) You and your partner should avoid conception (becoming pregnant or fathering children) for at least six months after your treatment with methotrexate has stopped.
• if you suffer from a problem of excessive drinking (alcoholism)
• if you have severe liver problems, including fibrosis, alcoholic liver disease and recent or active hepatitis (inflammation of the liver)
• if you have severe kidney problems, including conditions requiring kidney dialysis
• if you have any serious blood disorders including severe anaemia or abnormal numbers of blood cells such as low white cells (leucopenia) or low small blood cell numbers (platelets) causing (thrombocytopenia)
• if you have a medical condition or are receiving medication which lowers your resistance to infection
• if you are taking antibiotics which prevent the production of folic acid (vitamin B9) such as co-trimoxazole, which are used to treat bacterial infections
• if you have symptoms which may suggest an active infectious disease (e.g. fever, chills, achiness)
• if you are being treated with live vaccines
• if you have ulcer of the oral cavity and gut
• if you have inflammation of mouth or lips.

Even though some of the above may be obvious, it is important that your doctor is aware if any of them apply to you.

Important warning about the dose of Methotrexate 2.5 mg Tablets (methotrexate):

Take Methotrexate 2.5 mg Tablets only once a week for the treatment of rheumatic or skin diseases (RA, JIA and psoriasis or psoriatic arthritis).

Taking too much of Methotrexate 2.5 mg Tablets (methotrexate) may be fatal.

Please read section 3 of this leaflet very carefully.

If you have any questions, please talk to your doctor or pharmacist before you take this medicine.

Talk to your doctor, pharmacist or nurse before taking Methotrexate 2.5 mg Tablets if you:

• have any mild or moderate liver or kidney problems or blood disorders including anaemia
• have dependence on alcohol or abnormal liver function tests
• have gastro-intestinal (digestive) problems like stomach ulcers or suffer from inflammation and ulceration of the gut
• have or have ever suffered from mental illness
• have severe mouth ulcers
• have diarrhea
• have any symptoms or signs of infection
• have an inactive chronic infection, such as herpes zoster, tuberculosis, hepatitis B or C
• have excess fluid between the lungs and chest wall (pleural effusion) causing breathlessness or in the abdomen causing swelling of the stomach (ascites). These may affect the levels of methotrexate in your blood
• are receiving or intend to receive any vaccine, as methotrexate can reduce their effect
• have diabetes mellitus and are being treated with insulin
• are an elderly patient or a very young child or in poor physical condition
• develop a persistent cough or develop shortness of breath as it may be associated with serious lung disease
• have received or you are receiving radiotherapy or ultraviolet (UV) radiation concurrently
• 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.

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).

Methotrexate temporarily affects sperm and egg production. 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”.

Whilst being treated with this medicine your doctor will want to monitor your progress on a weekly basis until your therapy is stable. Thereafter, you will be monitored every 2 to 3 months, whilst taking the medicine. These checks may include taking blood and urine samples to check your blood cells and to make sure that your liver and kidneys are working properly. It is important that you do not miss any blood tests.

There may also be a chest x-ray and a physical examination to check for swelling of your lymph nodes (glands in your neck, armpits and groin). Any unusual swellings should also be reported to your doctor.

If the results of any of these tests are abnormal, treatment will only be resumed when all readings are back to normal.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This includes medicines obtained without a prescription. The effects of these medicines may change, especially if you are taking:

• NSAIDs (non-steroidal anti-inflammatory drugs) e.g. ibuprofen, indomethacin or azopropazone, phenylbutazone (for relief of pain or inflammation) including any preparations of these bought without a prescription. Taking these products together with Methotrexate 2.5 mg Tablets can increase its toxic effects
• aspirin or similar medicines (known as salicylates)
• diuretics (e.g. Bendroflumethiazide, loop diuretics like furosemide, hydrochlorothiazide or triamterene – water pills)
• phenytoin, carbamazepine, levetiracetam and valproate (for seizures)
• antibiotics (used to treat bacterial infections) including penicillin, sulphonamides, trimethoprim/sulfamethoxazole (as cotrimoxazole), neomycin, ciprofloxacin, doxycycline, tetracyclines, chloramphenicol
• nitrous oxide-based (a gas used in general anaesthesia)
• vaccinations / live virus vaccines
• oral hypoglycaemics (used for lowering blood sugar levels) like metformin
• olanzapine used for the treatment of schizophrenia
• pyrimethamine (medication against malaria)
• digoxin (used to treat heart failure)
• corticosteroids used for the treatment of arthritis, allergic reactions or skin diseases
• medication against cancer e.g. cisplatin, doxorubicin; 5-fluorouracil and procarbazine
• retinoids, e.g. acitretin (for psoriasis or skin disorders)
• immunosuppressant drugs such as leflunomide (used for suppression of inflammatory conditions) or ciclosporin
• probenecid, sulfinpyrazone (for gout)
• omeprazole, pantoprazole (for stomach ulcers, heartburn, reflux)
• theophylline (for asthma)
• vitamin preparations containing folic acid or similar products
• p-aminobenzoic acid used to treat skin disorders.
• radiotherapy
• sulfasalazine (used to treat arthritis)
• mercaptopurine (used to treat acute lymphocytic leukaemia)
• barbiturates and tranquilizers (central nervous system depressant used to treat insomnia and seizures)
• oral contraceptives (birth control pills)
• amidopyrine derivatives (used to treat fever)
• colestyramine (medicine used to treat high cholesterol);

You should not drink alcohol whilst you are taking this medicine as it increases the risk of liver damage.

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

Pregnancy

Do not use Methotrexate 2.5 mg Tablets 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.

It may also affect women’s periods; they may become less frequent or stop completely.

Methotrexate can affect sperm and egg production with the potential to cause birth defects. Do not use Methotrexate 2.5 mg Tablets if you are trying to become pregnant. You and your partner should avoid conception (becoming pregnant or fathering children) for at least six months after your treatment with methotrexate has stopped. Therefore, you must ensure that you are taking effective contraception for the whole of this period (see also section "Warnings and precautions").

As methotrexate may cause genetic mutations, all women who wish to become pregnant are advised to consult a genetic counselling centre, if possible already prior to therapy, and men should seek advice about the possibility of sperm preservation before starting therapy.

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.

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.

Breast-feeding

Methotrexate 2.5 mg Tablets should not be used during breast-feeding. Methotrexate passes into breast milk. Breast-feeding should be stopped prior to and during treatment with Methotrexate 2.5 mg Tablets.

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").

Methotrexate 2.5 mg Tablets may make you feel drowsy, dizzy, loss of co-ordination or may give you blurred vision. You should not drive or use machines when you first start to take this medicine until you are certain that you are not getting these side effects. If in any doubt, speak to your doctor before you drive or use machines.

These tablets contain lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

Use Methotrexate 2.5 mg Tablets only once a week for the treatment of rheumatoid arthritis, psoriasis etc. Using too much of Methotrexate 2.5 mg Tablets (methotrexate) may be fatal. Please read section 3 of this leaflet very carefully. If you have any questions, please talk to your doctor or pharmacist before you take this medicine.

Adults, the Elderly and Children

Your doctor will want to monitor your progress, usually every 2-3 months, whilst you are receiving Methotrexate 2.5 mg Tablets.

Before, during and after your treatment you may have tests, such as a chest X-ray, physical examination and blood tests to check that your liver and kidneys are working properly.

The recommended dose for Pregnancy related tumours is 0.25-1 mg /kg up to a maximum of 60 mg every 48 hours for four doses with Calcium Leucovorin rescue. Your doctor will tell you to repeat this treatment at seven-day intervals. Not less than four courses of treatment are usually necessary.

Lymphoma: The recommended dose is 3-30 mg/kg of methotrexate given by injection along with Calcium Leucovorin with the higher doses. It may also be given alongside other medicines as part of chemotherapy.

Burkitt’s lymphoma: The recommended dose is 15 mg/m² daily orally for five days. It may also be given alongside other medicines as part of chemotherapy.

The recommended dose is 10-60 mg/m² of methotrexate are usually given by injection by your doctor or nurse alongside other medicines as part of chemotherapy.

The recommended dose is 20-300 mg/kg (approximately 600-9,000 mg/m²) of methotrexate with Calcium Leucovorin rescue are used in the treatment of bone cancer. It may also be given alongside other medicines as part of chemotherapy.

The recommended dose is 20-100 mg/m² of methotrexate have been included in cyclical combination regimes for the treatment of advanced tumours.

The recommended dose is 240-1,080 mg/m² methotrexate with calcium Leucovorin are used in the treatment of head and neck cancers.

The recommended dose is up to 100 mg are usually given by injection by your doctor or nurse.

Leukaemia

The recommended dose is methotrexate 15 mg/m², parenterally or orally once weekly, in combination with other drugs appears to be the treatment of choice for maintenance of drug-induced remissions.

Meningeal leukaemia

The recommended dose is up to 15 mg, intrathecally, at weekly intervals, until the CSF appears normal (usually two to three weeks), have been found useful for the treatment of meningeal leukaemia.

Take Methotrexate 2.5 mg Tablet only once a week.

Adults

USUAL DOSE: between 10 and 25 mg by mouth (4 to 10 tablets) taken once a week on the same day each week. This should be adjusted according to your response to treatment and side effects.

Elderly: No dosage adjustment required.

Children: Not recommended for use in children.

Take Methotrexate 2.5 mg Tablet only once a week.

USUAL DOSE: between 7.5 and 20 mg (3 to 8 tablets) taken once a week on the same day each week.

These doses may alter as your condition changes.

Do not miss your appointments as these are necessary to ensure that Methotrexate 2.5 mg Tablets are used safely.

Your doctor may give you additional medication to help make sure that methotrexate does not collect in the kidneys.

Blood monitoring should be done for all patients treated with methotrexate. Close monitoring of the blood levels should be done including the complete blood counts, urine tests and in some cases blood methotrexate monitoring along with liver and kidney function tests to detect any problems.

The score line is only there to help you break the tablet if you have difficulty swallowing it whole.

If you have taken an overdose of methotrexate or more tablets than the doctor has told you to, you should get medical help immediately either by calling your doctor or by going to the nearest hospital casualty department. Always take the labelled medicine container with you, whether there are any Methotrexate 2.5 mg Tablets left or not.

Overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit that looks like coffee grounds, and decreased urinating.

Inappropriate intake resulting in overdose can sometimes lead to death.

The antidote in case of an overdose is calcium folinate.

If you forget to take a dose, take it as soon as you remember if this is within two days. However, if you have missed a dose by more than two days, please contact your doctor for advice. Do not take a double dose to make up for a forgotten dose.

Do not stop taking Methotrexate 2.5 mg Tablets unless your doctor tells you to. Should you need to stop taking Methotrexate Tablets, your doctor will have decided which is the best method for you.

Common: may affect up to1 in 10 people

• headache, dizziness, fatigue
• swelling or soreness of the mouth, throat and lips
• anorexia (eating disorder)
• feeling sick (nausea) or vomiting
• loose stools
• raised liver enzymes
• a skin rash with reddening of the skin
• hair loss
• decreased white blood cell count.
• Bacteria or fungal infection of hand and feet

Uncommon: may affect up to 1 in 100 people

• a lump in your neck, groin or armpits with associated backache, weight loss or night sweats
• decrease in the number of blood cells
• reduction in red blood cells which can make the skin pale and cause weakness or breathlessness
• reduction in blood platelets, which increases risk of bleeding or bruising
• nose bleed
• itching
• blistering and peeling of the top layer of the skin all over the body
• vaginal ulcers.

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

• raised blood sugar levels (diabetes mellitus)
• herpes zoster (shingles) which is a viral disease characterized by a painful skin rash with blisters
• depression
• confusion
• inability to move one half of the body
• fall in blood pressure
• clot in the veins which may cause tenderness and swelling of the lower extremities which may travel through blood vessels to lungs causing chest pain or difficulty in breathing.
• clot in the retinal vein of eye
• blood clot in an artery
• blood clot in the brain's venous sinuses causing swelling and bleeding (hemorrhage) in the brain
• difficulty in breathing
• throat infection
• swelling of the gums
• mouth ulcer, stomach or intestinal ulcers, bleeding or inflammation of the intestine
• symptoms of abdominal pain, cramping, diarrhoea, dehydration, fever, nausea, vomiting and weight loss. These could be signs of a condition known as enteritis (inflammation of the intestine)
• decreased absorption from intestines
• sensitivity to light
• acne
• appearance of lightened patches on the skin
• hives
• skin ulcers and painful erosions of inflamed areas, in psoriasis patients
• muscle pain, joint pain
• weakening or softening of bones
• an increase in rheumatic nodules
• loss of interest in, or inability to have sex
• menstrual disorders
• impotence.

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

• immune disorder
• fatigue
• irritation
• difficulty with speech
• blurred vision/ visual disturbance
• eye infection
• chest pain or tightness of chest, with difficulty in breathing
• lung infection (Pneumonia)
• vomiting blood
• small bruises on the skin caused by blood leaking from broken blood vessels
• boils
• vasculitis (pain or redness of the blood vessels)
• dilatation of small blood vessels causing focal red lesions
• low sperm count
• abnormally high levels of nitrogen-containing compounds in the blood
• pain or difficulty in passing urine
• blood in urine
• elevation of urea and/or creatinine in the blood
• infertility
• enlargement of breasts in men
• vaginal bleeding
• dry cough
• lymphoproliferative disorders (excessive growth of white blood cells).
• sensation of numbness or tingling, having less sensitivity to stimulation than normal

Not known: frequency cannot be estimated from the available data

• liver failure
• severe reduction in blood cells which can cause weakness, bruising or make infections more likely
• high amount of white blood cell
• bone marrow producing unusually large, structurally abnormal, immature red blood cells causing deficiency of healthy red blood cells in blood (megaloblastic anaemia)
• disorder in formation of blood cellular components
• deficiency in type of white blood cells making you vulnerable to picking up infections
• bone marrow producing inadequate number of new blood cells thereby causing tiredness, shortness of breath, rapid heart rate, unexplained bruising, nose bleeds, headache and fever
• bleeding or haemorrhage from various sites and small red or purple spot caused by bleeding into the skin
• disease affecting the lymph nodes
• ulcers in urinary bladder
• asthma
• unusual sensations in the head
• mood alteration
• loss of intellectual functions such as thinking, reasoning
• drowsiness
• general feeling of illness
• other metabolic changes
• fits (seizures)
• deficiency of blood supply to the heart muscle
• fluid in lung
• syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses
• pain and inflammation of the body's mucous membrane
• inflammation of vagina
• discharge from the vagina,
• increased risk of toxic reaction
• bone damage in the jaw (secondary to excessive growth of white blood cells)
• bleeding from the lungs*
• abnormal red blood cell function
• ringing in the ears
• abdominal pain
• inflammation of Pancreas characterized by severe abdominal pain
• indigestion
• black or tarry stools
• difficulty sleeping
• change in sense of taste
• the need to pass urine more often than usual
• changes in skin and nail colouration
• enhanced pigmentation of the skin redness and shedding of skin
• tiredness and lack of energy
• excessive accumulation of fluid causing swelling
• severe skin reaction
• painful bumps under the skin
• intensely itchy blisters filled with a watery fluid
• inflammation of the skin around the nail, which can occur suddenly
• damaged skin becomes inflamed on re-exposure to radiation and sunlight
• reappearance previously resolved infections
• excess accumulation of fluid (edema) in the brain
• paralysis
• disease of the retina which results in impairment or loss of vision
• nail separation from the skin underneath
• inflammation of the walls of blood vessels, resulting from an allergic reaction
• changes in the blood levels of chemicals and salts

*(has been reported for methotrexate used in patients with underlying rheumatologic disease).

In a small number of patients methotrexate may cause serious side effects and on rare occasions, death. You should contact your doctor immediately if you notice any serious side effects. Certain other unwanted effects can only be detected by your doctor, these include blood disorders, and changes in liver and kidney function or bone density.

Your doctor will take blood samples to check for these problems and may ask you to have a small sample of your liver taken for testing (liver biopsy).

If you get any side effects, talk to your doctor or pharmacist. 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.

• The active substance is methotrexate. Each tablet contains methotrexate sodium equivalent to 2.5 mg methotrexate
• The other ingredients are lactose monohydrate, sodium hydroxide, magnesium stearate and starch, pregelatinised.

Methotrexate 2.5 mg Tablets are round, biconvex, yellow tablets, engraved with "2.5" on one side. Scored in half on the other side and engraved with "M" above the score line and "1" below it. They are supplied in bottles containing 28 or 100 tablets or blister packs containing 24, 28 or 30 Tablets.

Not all pack sizes may be marketed.