Methofill

Patient Information Leaflet

Methofill, 2.5 mg, tablets
Methofill, 10 mg, tablets
Methotrexatum
Methofill tablets should be taken once a week
Please read this leaflet carefully before taking this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you personally. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, inform your doctor or pharmacist (see section 4).

Table of Contents

1. What Methofill is and what it is used for
2. Important information before taking Methofill
3. How to take Methofill
4. Possible side effects
5. How to store Methofill
6. Contents of the pack and other information

1. What Methofill is and what it is used for

Methofill contains the active substance methotrexate. Methotrexate is an antimetabolite and an immunosuppressive agent (a medicine that affects cell proliferation and reduces the activity of the immune system).
Methotrexate is used in the treatment of:

• active rheumatoid arthritis in adults,
• severe psoriasis, particularly plaque-type psoriasis, in patients who have not responded to other treatments,
• active psoriatic arthritis in adult patients,
• acute lymphoblastic leukaemia in adults, adolescents, and children aged 3 years and above.

Your doctor will explain how Methofill can help in your particular condition.

2. Important information before using Methofill

When not to use Methofill

• 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 renal impairment (or the doctor classifies the disorder as severe);
• if the patient has liver function disorders;
• if the patient has blood disorders such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia;
• if the patient abuses alcohol;
• if the patient has a weakened immune system;
• if the patient suffers from a serious infection, such as tuberculosis or HIV;
• if the patient has gastric or intestinal ulcers;
• if the patient has oral mucositis or oral ulcers;
• if the patient is breastfeeding and additionally for non-oncological indications (in non-oncological treatment);
• if the patient is pregnant (see section "Pregnancy, breastfeeding and fertility");
• if the patient has recently been vaccinated with a live vaccine or is due to receive one.

Recommended monitoring tests and precautions
Even when methotrexate is used in low doses, serious adverse effects may occur. To detect them early, the doctor must perform monitoring tests and laboratory examinations.
Before starting treatment:
Prior to initiating treatment, a blood test will be performed to check whether the patient has an adequate number of blood cells. Blood will also be tested for liver function to determine whether the patient has hepatitis. Additionally, serum albumin (a blood protein), presence of hepatitis (liver infection), and kidney function will be assessed. The doctor may also decide to perform other liver tests. Some of these may include imaging tests, while others may require a small tissue sample from the liver for more detailed examination. The doctor may also check whether the patient has tuberculosis, order a chest X-ray, or perform lung function tests.
During treatment:
The doctor may perform the following tests:

• examination of the mouth and throat for mucosal changes such as inflammation or ulceration;
• blood tests including complete blood count to assess blood cell counts and measurement of serum methotrexate concentration;
• blood tests to monitor liver function;
• imaging tests to monitor liver status;
• liver biopsy (taking a small tissue sample from the liver) for more detailed examination;
• blood tests to monitor kidney function;
• monitoring of the respiratory tract and, if necessary, lung function tests.
  It is very important that the patient attends all scheduled check-ups. If any of these test results are abnormal, the doctor will adjust the treatment accordingly.

Elderly patients
Elderly patients treated with methotrexate should be closely monitored by the doctor to allow for early detection of any adverse effects. Age-related liver and kidney function disorders, as well as low folate reserves in older age, require relatively low doses of methotrexate.

Warnings and precautions
Important warning regarding the dose of Methofill (methotrexate):
Methotrexate tablets must be taken only once a week in the treatment of rheumatic or skin diseases (rheumatoid arthritis and psoriasis or psoriatic arthritis).
Taking too high a dose of Methofill (methotrexate) can be fatal.
Please read section 3 of this leaflet carefully.
If you have any questions, speak with your doctor or pharmacist before taking this medicine.

Before starting Methofill, inform your doctor or nurse:

• if the patient has diabetes treated with insulin;
• if the patient has inactive, chronic infections (e.g. tuberculosis, hepatitis B or C virus, shingles), as these may flare up;
• if the patient has ever had liver or kidney disease;
• if the patient has lung function disorders;
• if the patient has significant overweight;
• if the patient has abnormal fluid accumulation in the abdominal cavity (ascites) or around the lungs (pleural effusion);
• if the patient is dehydrated or suffers from conditions causing dehydration (vomiting, diarrhea, constipation, oral mucositis).

Methotrexate may increase skin sensitivity to sunlight. Avoid intense sun exposure and do not use sunbeds or tanning lamps without consulting your doctor. To protect the skin from strong sunlight, wear appropriate clothing or use a high-protection sunscreen.
If the patient previously had skin problems after radiotherapy (radiation dermatitis) or sunburn, these reactions may recur during methotrexate treatment (recall reaction).
Psoriatic skin lesions may worsen during methotrexate treatment if the patient is exposed to UV light.
In patients receiving low-dose methotrexate, lymph node enlargement (lymphadenopathy) may occur, and treatment should be discontinued in such cases.
Cases of acute pulmonary hemorrhage have been reported in patients with underlying rheumatological disease during methotrexate treatment. If the patient experiences hemoptysis (coughing up blood-stained sputum), seek immediate medical attention.
Diarrhea is a possible adverse effect of Methofill and requires discontinuation of treatment. If diarrhea occurs, speak with your doctor.
In patients with cancer receiving methotrexate, certain brain disorders (encephalopathy/leukoencephalopathy) have been reported. Such adverse effects cannot be ruled out when methotrexate is used to treat other diseases.
Methotrexate temporarily affects sperm and egg cell production. Methotrexate may cause miscarriage and severe congenital malformations. The patient should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends. Patients should avoid conceiving a child during methotrexate treatment and for at least 3 months after treatment ends. See also section "Pregnancy, breastfeeding and fertility".
Recommended monitoring tests and precautions
Severe adverse effects may occur even when methotrexate is used in low doses. The doctor must perform examinations and laboratory tests to detect these effects as early as possible.
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, contact the doctor immediately, as these may be symptoms of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).
Children and adolescents
Children and adolescents treated with methotrexate should be under particularly careful medical observation to allow for rapid detection of significant adverse effects.
This medicine is not recommended for use in children under 3 years of age, as experience in this age group is insufficient.

Methofill and other medicines
Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including those obtained without a prescription, herbal remedies, or natural supplements. Remember to inform your doctor that you are being treated with methotrexate if another medicine is prescribed during treatment.
It is especially important to inform the doctor about the use of the following medicines:

• other medicines used for rheumatoid arthritis or psoriasis, such as leflunomide, azathioprine (also used to prevent organ transplant rejection), sulfasalazine (also used in the treatment of ulcerative colitis);
• cyclosporine (used to suppress the immune system);
• non-steroidal anti-inflammatory drugs or salicylates (painkillers and/or anti-inflammatory drugs such as acetylsalicylic acid, diclofenac, ibuprofen, or pyrazolones);
• live vaccines;
• diuretics that reduce fluid retention;
• blood glucose-lowering medicines such as metformin;
• retinoids (used in the treatment of psoriasis and other skin diseases);
• antiepileptic drugs (to prevent seizures);
• barbiturates (sleeping pills);
• sedatives;
• oral contraceptives;
• probenecid (used in the treatment of gout);
• antibiotics;
• pyrimethamine (used to prevent and treat malaria);
• vitamin preparations containing folic acid;
• proton pump inhibitors (used to treat heartburn, ulcers, and certain other stomach conditions);
• theophylline (for breathing problems), mercaptopurine (in the treatment of certain types of leukemia);
• anticancer drugs (such as doxorubicin and procarbazine during high-dose methotrexate therapy);
• metamizole (synonyms: novaminsulfone and dipyrone) (a strong painkiller and/or antipyretic).

Methotrexate Accord with food, drink, and alcohol
This medicine can be taken with or without food. After taking the dose, drink some water to ensure the full dose has been taken and that no methotrexate residue remains in the mouth. Do not drink alcohol during methotrexate treatment, and avoid excessive consumption of coffee, caffeine-containing beverages, and black leaf tea. The patient should ensure adequate fluid intake during methotrexate treatment, as dehydration (reduced body water) may worsen methotrexate's adverse effects.

Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before taking this medicine.
Pregnancy
Do not use Methofill during pregnancy unless prescribed by a doctor for oncological treatment.
Methotrexate may cause congenital malformations, harm the unborn child, or cause miscarriage. This is associated with deformities of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that methotrexate is not given to pregnant women or women planning pregnancy, unless used in oncological treatment.
For non-oncological indications, pregnancy should be excluded in women of childbearing age before starting treatment, e.g. by using pregnancy tests.
Do not take methotrexate tablets if the patient plans to become pregnant. Avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends. Therefore, 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, contact the doctor immediately. If pregnancy occurs during treatment, advice should be sought regarding the risk of harmful effects on the child. If the patient wishes to become pregnant, she should speak with her doctor, who may refer her to a specialist before planned treatment initiation.
Breastfeeding
Do not breastfeed during treatment, as methotrexate passes into breast milk.
The patient must stop breastfeeding if the doctor considers methotrexate treatment absolutely necessary during this period.
Fertility
Male fertility
Available data do not indicate an increased risk of developmental abnormalities or miscarriage if the father takes methotrexate at doses below 30 mg/week. However, the risk cannot be completely ruled out, and there is no information regarding higher doses of methotrexate.
Methotrexate may have genotoxic effects. This means the drug may cause genetic mutations. Methotrexate may affect sperm production, which may lead to congenital abnormalities.
Avoid conception or donating sperm during methotrexate treatment and for at least 3 months after treatment ends. Because methotrexate treatment at higher doses, commonly used in cancer therapy, may cause infertility and genetic mutations, male patients treated with methotrexate at doses above 30 mg/week may consider sperm preservation before starting treatment (see also section "Warnings and precautions").
Before taking any medicine, consult your doctor or pharmacist.
Driving and operating machinery
Warning: this medicine may affect reaction ability and the ability to drive vehicles.
During treatment with Methofill, adverse effects affecting the central nervous system may occur, such as fatigue or dizziness. In some cases, this may affect the ability to drive vehicles and operate machinery. If fatigue or dizziness occurs, do not drive or operate machinery.
Methofill contains lactose
Methofill contains lactose. If the doctor has diagnosed the patient with an intolerance to certain sugars, the patient should contact the doctor before taking this medicine.

3. How to use Methofill

Methofill should only be prescribed by physicians who are familiar with the properties and mode of action of the drug.
This medicine should always be taken according to the instructions of the physician or pharmacist. In case of doubts, consult your doctor or pharmacist.
Improper use of Methofill may result in serious adverse effects, and even death.
The duration of treatment is determined by the treating physician. Treatment of rheumatoid arthritis, severe psoriasis, and severe psoriatic arthritis with Methofill is long-term therapy.

Recommended dosage
Your doctor will decide the appropriate dose of Methofill based on the disease being treated, its severity, and your overall health status. You must strictly follow your doctor's instructions regarding dosage and timing of administration.

Dosage in rheumatic and skin diseases (RA, JIA, psoriasis, or psoriatic arthritis)
Methofill should be taken once weekly only.
You should agree with your doctor on the most suitable day of the week for taking the medicine.

Dosage in rheumatoid arthritis in adults: The usual initial dose is 7.5–15 mg orally, once a week.
Dosage in psoriasis and psoriatic arthritis: The usual initial dose is 7.5–15 mg orally, once a week.
Your doctor may increase the dose if the current dose is not effective but is well tolerated.
Your doctor may adjust the dose depending on the response to treatment and any adverse effects.

Dosage in acute lymphoblastic leukemia (ALL)
Your doctor will inform you of the dose and schedule for taking the medicine.
You must strictly follow the prescribed dosage. The dose should be taken orally, once a week.

Use in children and adolescents
The doctor will calculate the required dose based on the child's body surface area (m²), and the dose will be expressed in mg/m².

Elderly patients
Due to reduced liver and kidney function, as well as lower folate stores in this patient group, a lower dose should be used appropriately.

Methofill 10 mg tablets: The score line is intended only to facilitate breaking the tablet if difficulty swallowing the whole tablet occurs.

Safe handling of Methofill
Appropriate procedures for safe handling of cytotoxic agents must be observed. Disposable gloves should be worn when handling methotrexate tablets. Pregnant women should avoid contact with methotrexate tablets if possible.

Taking more than the recommended dose of Methofill
Follow your doctor's dosing instructions exactly. Never change the dose on your own. If you suspect that a patient (or someone else) has taken an excessive dose of Methofill, contact your doctor immediately or go to the nearest hospital emergency department. The doctor will decide whether any treatment is required.
Methotrexate overdose may cause serious reactions. Symptoms of overdose may include bleeding, unusual weakness, oral ulceration, nausea, vomiting, black or bloody stools, coughing up blood, coffee-ground-like bloody vomit, and reduced urine output. See also section 4, "Possible adverse effects".
When visiting the doctor or hospital, bring the medicine packaging with you. The antidote for overdose is calcium folinate.

Missed dose of Methofill
Never take a double dose to make up for a missed dose. Continue taking the prescribed dose as directed. Consult your doctor for advice.

Stopping Methofill
Do not stop taking Methofill without first discussing it with your doctor. If you suspect a serious adverse effect, contact your doctor immediately.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
You should contact your doctor immediately if you suddenly develop wheezing, difficulty
breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting the whole
body).
You should contact your doctor immediately if any of the following side effects occur:

• breathing problems (including general feeling of illness, dry, irritating cough, shortness of breath, difficulty breathing, chest pain or fever)
• coughing up or spitting blood*
• severe peeling or blistering of the skin
• unusual bleeding (including vomiting blood), bruising or nosebleeds
• nausea, vomiting, abdominal discomfort or severe diarrhoea
• mouth ulcers
• black or tarry stools
• blood in the urine or faeces
• small red spots on the skin
• fever, sore throat, flu-like symptoms
• yellowing of the skin (jaundice) or dark urine
• pain or difficulty passing urine
• thirst and (or) frequent urination
• seizures (convulsions)
• loss of consciousness
• blurred or reduced vision
• severe tiredness *Reported with methotrexate used in patients with underlying rheumatological disease.

The following side effects have also been reported:
Very common (may affect more than 1 in 10 people):

• loss of appetite, nausea, vomiting, stomach pain, indigestion, inflammation and ulceration of the mouth and throat
• blood tests showing increased liver enzyme activity

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

• infections
• reduced blood cell production leading to decreased numbers of white and (or) red blood cells and (or) platelets (leucopenia, anaemia, thrombocytopenia)
• headache, fatigue, dizziness
• lung inflammation with dry cough, shortness of breath and fever
• diarrhoea
• skin rash, redness and itching of the skin

Uncommon (may affect up to 1 in 100 people):

• lymphoma (lump in the neck, groin or armpit associated with back pain, weight loss or night sweats)
• severe allergic reactions
• diabetes
• depression
• dizziness, confusion, seizures
• lung damage
• ulcers and bleeding in the gastrointestinal tract
• liver disorders, decreased blood protein levels
• urticaria, sunburn-like reactions due to increased sensitivity of the skin to sunlight, brown skin discoloration, hair loss, increased number of rheumatoid nodules, shingles, painful psoriasis, slow healing of wounds
• joint or muscle pain, osteoporosis (weakening of bones)
• kidney disease, inflammation or ulceration of the bladder (possibly with blood in the urine), painful urination
• inflammation and ulceration of the vagina

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

• blood disorder characterised by the presence of very large red blood cells (megaloblastic anaemia)

• mood swings

• reduced movement, including weakness affecting only the left or right side of the body

• severe vision disturbances

• pericarditis, fluid accumulation in the pericardial sac

• low blood pressure, blood clots

• tonsillitis, breathing arrest, asthma

• pancreatitis, inflammation of the gastrointestinal tract, bloody stools, gingivitis, indigestion

• acute hepatitis

• nail discoloration, acne, red or purple spots caused by bleeding from blood vessels

• worsening of psoriasis during UV light therapy

• skin changes resembling sunburn or skin inflammation after radiotherapy

• bone fractures

• kidney failure, reduced or absent urine production, abnormal blood electrolyte levels

• impaired sperm production, menstrual disorders

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

• systemic viral, fungal or bacterial infections
• serious bone marrow disorder (anaemia), swollen lymph nodes
• lymphoproliferative disorders (excessive white blood cell growth)
• insomnia
• pain, muscle weakness, altered sense of taste (metallic taste), inflammation of the membrane surrounding the brain causing paralysis or vomiting, numbness or tingling/less than normal sensitivity to stimuli
• movement disorders of muscles used for speech, difficulty speaking, speech disturbances, drowsiness or fatigue, feeling disoriented, strange sensations in the head, brain swelling, ringing in the ears
• redness of the eyes, damage to the retina of the eye
• fluid accumulation in the lungs, lung infections
• vomiting blood, severe gastrointestinal complications
• liver failure
• nail infections, separation of the nail plate from the nail bed, boils, dilation of small blood vessels, damage to skin blood vessels, allergic vasculitis
• protein in the urine
• loss of libido, erectile dysfunction, hot flushes, infertility, breast enlargement in men (gynaecomastia)
• fever

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

• pathological change in the white matter of the brain (leukoencephalopathy)
• haemorrhages
• bleeding from the lungs*
• redness and peeling of the skin
• damage to the jawbone (secondary to excessive white blood cell growth)
• swelling *Reported with methotrexate used in patients with underlying rheumatological disease.

Methotrexate may reduce the number of white blood cells and thereby weaken the immune
defence. If you notice any signs of infection, such as fever or a marked deterioration in your general
health, or fever with local signs of infection such as sore throat/tonsillitis or mouth inflammation, or
problems passing urine, you should contact your doctor immediately. A blood test will be performed
to check for reduced white blood cell count (agranulocytosis). It is important to inform your doctor
about all medicines you are taking.
Methotrexate can cause serious (sometimes life-threatening) side effects. Therefore, your doctor will
carry out tests to check for any changes in the blood (e.g. low white blood cell count, low platelet
count, lymphomas), kidneys or liver.
Reporting of side effects
If you experience any side effects, including any not listed in this leaflet, tell your doctor or
pharmacist. Side effects can be reported directly to the Department of Monitoring Adverse Drug
Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
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 authorisation holder.

5. How to store Methofill

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the blister pack/outer carton after EXP.
The expiry date refers to the last day of the specified month.
No special temperature storage conditions are required for this medicine.
Blister pack: store the blister in the outer packaging to protect it from light.
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 Methofill contains
The active substance is methotrexate.
One tablet contains 2.5 milligrams of methotrexate.
One tablet contains 10 milligrams of methotrexate.
The other ingredients are: calcium hydrogen phosphate anhydrous, lactose monohydrate,
sodium carboxymethyl starch (type A), microcrystalline cellulose, talc, magnesium stearate
(E470b).

What Methofill looks like and contents of the pack
Methofill 2.5 mg are yellow, round, biconvex, uncoated tablets with a diameter of
4.5 ± 0.2 mm, smooth on both sides.
Methofill 10 mg are yellow, uncoated, biconvex, capsule-shaped tablets with a length of
10.0 ± 0.2 mm and width of 5.0 ± 0.2 mm, featuring a division line on one side and smooth on the other.
The tablets are packed in blisters made of orange PVC coating and aluminium foil.
PVC/Aluminium blister
Pack sizes: 10, 12, 15, 20, 24, 25, 28, 30, 50 or 100 tablets.
Single-dose blister PVC/Aluminium.
Pack sizes: 10x1, 12x1, 15x1, 20x1, 24x1, 25x1, 28x1, 30x1, 50x1 or 100x1.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
Taśmowa Street 7
02-677 Warsaw
Tel: +48 22 577 28 00

Manufacturer/Importer
Accord Healthcare B.V.
Winthontlaan 200
3526 KV Utrecht
The Netherlands
Accord Healthcare Polska Sp. z o.o.
Lutomierska Street 50
95-200 Pabianice
Poland

This medicinal product is authorised in the European Economic Area (EEA) under the following names: