Methofill

Patient Information Leaflet

Methofill, 50 mg/ml, solution for injection in prefilled syringe
Methotrexatum
Please read all of this leaflet carefully before using this medicine, because 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, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm someone else, even if their symptoms are the same as yours.
• If you experience any adverse reactions, including any possible side effects not listed in this leaflet, inform your doctor, pharmacist, or nurse (see section 4).

Table of contents

1. What Methofill is and what it is used for
2. What you need to know before you use Methofill
3. How to use 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

The active substance in Methofill is methotrexate.
Methotrexate has the following properties:

• Inhibits the growth of certain rapidly dividing cells
• Reduces the activity of the immune system (the body's defence mechanisms)
• Has anti-inflammatory effects

Indications for Methofill:

• Active rheumatoid arthritis in adult patients,
• Polyarticular-course juvenile idiopathic arthritis in children and adolescents, when response to non-steroidal anti-inflammatory drugs is inadequate,
• Severe psoriasis resistant to treatment, in which an adequate response has not been achieved with phototherapy, PUVA therapy, or retinoids, and severe psoriatic arthritis in adult patients,
• Mild to moderate Crohn's disease in adult patients when adequate treatment with other medications is not possible.

Rheumatoid arthritis (RA) is a chronic disease classified as a collagenosis, characterized by inflammation of the synovial membranes lining the joints. These membranes produce fluid that acts as a lubricant for many joints. Inflammation causes thickening of the membranes and joint swelling.
Juvenile arthritis occurs in children and adolescents under 16 years of age. Polyarticular forms are defined by involvement of five or more joints within the first six months of disease.
Psoriatic arthritis refers to joint inflammation, particularly in the fingers and toes, associated with psoriatic skin and nail changes.
Psoriasis is a common chronic skin disease characterized by red patches covered with thick, dry, silvery, tightly adherent scales.
Methofill modifies and slows the progression of the disease.
Crohn's disease is a type of inflammatory bowel disease that can affect any part of the gastrointestinal tract, causing symptoms such as abdominal pain, diarrhoea, vomiting, or weight loss.

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 liver, kidney, or blood disease;
• if the patient regularly consumes large amounts of alcohol;
• if the patient has a severe infection, such as tuberculosis, HIV infection, or other immunodeficiency syndromes;
• if the patient has ulcers in the mouth, stomach, or intestines;
• if the patient is receiving a vaccine containing live microorganisms at the same time;
• if the patient is pregnant or breastfeeding (see section "Pregnancy, breastfeeding and fertility").

Warnings and precautions
Before starting treatment with Methofill, discuss with your doctor or pharmacist:

• if the patient is elderly, weakened, or in poor general health;
• if the patient has impaired liver function;
• if the patient has dehydration (lack of water in the body);
• if the patient has diabetes and is being treated with insulin.

Cases of acute pulmonary haemorrhage have been reported in patients with underlying rheumatological disease during methotrexate treatment. If the patient experiences haemoptysis (coughing up blood), seek immediate medical advice.

Special precautions for the use of Methofill
Methotrexate temporarily impairs the production of sperm and egg cells; this effect usually reverses in most cases. Methotrexate may cause miscarriage and severe congenital malformations. Female patients should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends. Male patients should avoid fathering 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:
Even when methotrexate is used in 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 treatment, blood tests will be performed to check whether the patient has an adequate number of blood cells. Blood will also be tested for liver function to rule out hepatitis. Additionally, serum albumin (a blood protein), presence of liver inflammation (liver infection), and kidney function will be assessed. The doctor may also decide to perform other liver tests. Some of these may include imaging studies, while others may require a small liver tissue sample (biopsy) for more detailed examination. The doctor may also check for 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 full blood count to assess blood cell counts and measurement of methotrexate serum concentration;
• blood tests to monitor liver function;
• imaging tests to monitor liver status;
• liver biopsy to examine liver tissue in more detail;
• 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 receiving methotrexate should be closely monitored by the doctor to detect any adverse effects as early as possible. Age-related impairments in liver and kidney function, as well as lower folate reserves in older age, require relatively low doses of methotrexate.

Methotrexate may affect the immune system, vaccination outcomes, and immunological test results. It may lead to reactivation of latent chronic infections (e.g., shingles, tuberculosis, hepatitis B or C virus). Do not use vaccines containing live microorganisms while taking Methofill.

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.

During methotrexate treatment, a recurrence of radiation-induced skin inflammation or sunburn (so-called "recall reaction") may occur. Skin lesions associated with psoriasis may worsen during UV light exposure and concurrent methotrexate administration.

Lymph node enlargement (lymphadenopathy) may occur. In such a case, treatment should be discontinued.

Diarrhoea may be a sign of toxic effects of Methofill and requires treatment interruption. If the patient develops diarrhoea, inform the doctor immediately.

Cases of encephalopathy (brain disorder)/leukoencephalopathy (a disorder affecting the white matter of the brain) have been reported in oncology patients receiving methotrexate; this cannot be excluded in patients receiving methotrexate for other indications.

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, or personality changes, contact the doctor immediately, as these may be symptoms of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML).

Methofill with other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take. This includes all medicines, including those the patient intends to take in the future.

Concurrent use of certain medicines may affect the action of Methofill:

• antibiotics (used to prevent and treat certain infections), e.g.: tetracyclines, chloramphenicol, non-absorbable broad-spectrum antibiotics, penicillins, glycopeptides, sulfonamides, ciprofloxacin, and cephalothin (sulphur-containing drugs used to prevent and treat certain infections);
• non-steroidal anti-inflammatory drugs or salicylates (painkillers and/or anti-inflammatory medicines);
• probenecid (used in the treatment of gout);
• weak organic acids such as loop diuretics (diuretics), or certain medicines used for pain or inflammatory conditions (e.g. acetylsalicylic acid, diclofenac, and ibuprofen), and pyrazoles;
• medicinal products that may adversely affect bone marrow function, e.g. trimethoprim-sulfamethoxazole (a bactericidal agent) or pyrimethamine;
• other medicines used in the treatment of rheumatoid arthritis, such as leflunomide, sulfasalazine, and azathioprine;
• cyclosporine (an immunosuppressive medicine);
• mercaptopurine (a cytostatic medicine);
• retinoids (medicines for psoriasis and other skin diseases);
• theophylline (a medicine for asthma and other lung diseases);
• proton pump inhibitors (used for stomach disorders, such as omeprazole and pantoprazole);
• hypoglycaemic agents (medicines that lower blood sugar levels).

It is especially important to inform the doctor about the use of:

• metamizole (synonyms: dipyrone and novaminsulfone) (a strong painkiller and/or antipyretic).

Vitamin products containing folic acid should only be used if recommended by a doctor, as they may reduce the effectiveness of methotrexate.

Do not receive vaccinations with live vaccines.

Methofill with food, drink, and alcohol
During treatment with Methofill, avoid consuming alcohol as well as large amounts of coffee, caffeine-containing beverages, and black tea.

Pregnancy, breastfeeding and fertility
Pregnancy
Do not use Methofill if the patient is pregnant or trying to become pregnant. Methotrexate may cause congenital malformations, harm the unborn child, or cause miscarriage. This is associated with developmental abnormalities of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that women who are pregnant or planning pregnancy do not take methotrexate. If the patient is of childbearing age, pregnancy must be definitively ruled out before starting treatment, using appropriate measures such as a pregnancy test. The patient should avoid becoming pregnant during methotrexate treatment and for at least 6 months after treatment ends, using reliable contraception methods throughout this period (see also section "Warnings and precautions").

If the patient becomes pregnant during treatment or suspects she may be pregnant, she should consult her doctor immediately. The patient should seek advice regarding the potential harmful effects of treatment on the child.

If the patient plans to become pregnant, she should consult her treating doctor, who may refer her to a specialist for pre-treatment counselling.

Fertility in men
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 completely ruled out. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm and lead to congenital malformations. Therefore, the patient should avoid impregnating his partner and must not be a sperm donor during methotrexate treatment and for at least 3 months after treatment ends.

Breastfeeding
Breastfeeding must be discontinued before starting and during treatment with Methofill.

Driving and operating machinery
During treatment with Methofill, adverse effects on the central nervous system may occur, such as fatigue and dizziness. Therefore, the ability to drive motor vehicles and/or operate machinery may be impaired in some cases. If the patient feels drowsy or fatigued, driving or operating machinery is not allowed.

Methotrexate Accord contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. the medicine is considered "sodium-free".

3. How to use Methofill

The medicine should always be used as directed by the physician. In case of doubt, consult your
doctor or pharmacist.
The physician decides on the dosage, which is individually adjusted to the patient.
Therapeutic effects are usually noticeable only after 4–8 weeks of treatment.
Methofill is administered subcutaneously (under the skin) by a physician or healthcare professional,
or under their supervision, only once a week. The day for administration should be agreed upon
by the patient and the physician.
Important warning regarding dosing of Methofill (methotrexate):
In the treatment of rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, psoriasis, and
Crohn's disease, Methofill must be used only once a week. Overdosing on Methofill (methotrexate)
can be fatal. Please read section 3 of this leaflet carefully. If you have any questions before using
this medicine, consult your doctor or pharmacist.

Use in children and adolescents
The physician determines the appropriate dose for children and adolescents with polyarticular juvenile
idiopathic arthritis.
Methofill is not recommended for use in children under 3 years of age due to insufficient experience
in this age group.

Method and timing of administration
Methofill is injected once a week.
The duration of treatment is determined by the treating physician. Treatment of rheumatoid arthritis,
juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis, and Crohn's disease with Methofill
is long-term.
At the beginning of treatment, Methofill may be administered by medical personnel. However, the
physician may decide that the patient is capable of self-injecting Methofill. The patient will then be
properly trained accordingly. Never attempt self-injection without prior training.
Please refer to the instructions provided at the end of this leaflet.
Remember to use the entire contents of the pre-filled syringe.
Disposal procedures must be equivalent to those for other cytostatic drugs and in accordance with
local regulations. Pregnant women should not use or administer Methofill.
Avoid contact of methotrexate with skin surfaces or mucous membranes. In case of contamination,
immediately flush the affected area thoroughly with water.

Accidental overdose of Methofill
If more than the recommended dose has been taken, inform your doctor immediately.

Missed dose of Methofill
Do not take a double dose to make up for a missed dose.

Stopping Methofill treatment
If you stop taking Methofill, inform your doctor immediately.
If you feel that the effect of Methofill is too strong or too weak, consult your doctor or pharmacist.

4. Possible adverse effects

Like any medicine, this medicine can cause adverse effects, although not everyone will experience them.
The frequency and severity of adverse effects depend on the dose size and frequency of administration.
Since severe adverse effects may occur even after administration of small doses, regular medical examinations are necessary.
The treating physician should order tests to rule out abnormalities in blood parameters (e.g. low white blood cell count, low platelet count, and lymphoma) as well as changes in the liver and kidneys.
You must inform the doctor immediately if the patient develops any of the following symptoms, as they may indicate severe, potentially life-threatening adverse effects requiring urgent treatment:

• persistent, non-productive dry cough, dyspnea, and fever; these may be symptoms of pneumonitis [common]
• hemoptysis, i.e. coughing up blood-streaked sputum; these may be symptoms of pulmonary hemorrhage [frequency not known]
• signs of liver damage such as yellowing of the skin and whites of the eyes (jaundice); methotrexate may cause chronic liver damage (liver cirrhosis), scar tissue formation (liver fibrosis), fatty liver degeneration (hepatic steatosis) [all uncommon], hepatitis (acute hepatitis) [rare], and liver failure [very rare]
• allergic reactions such as skin rash, including red, itchy skin, swelling of hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty

swallowing or breathing and a feeling of impending fainting; these may be symptoms of severe
allergic reactions or anaphylactic shock [rare]

• signs of kidney damage such as swelling of hands, ankles, or feet, or changes in frequency of urination or reduced volume (oliguria) or absence of urine (anuria); these may be symptoms of kidney failure [rare]
• signs of infection such as fever, chills, malaise, sore throat; methotrexate may increase susceptibility to infections. Severe infections such as a specific type of pneumonia (pneumonia caused by Pneumocystis jirovecii) or blood poisoning (sepsis) may occur [rare]
• symptoms such as: weakness on one side of the body (stroke) or pain, swelling, redness and warmth in one leg (deep vein thrombosis). This may be due to a blood clot causing occlusion of a blood vessel (thromboembolic event) [rare]
• fever and severe worsening of general health or sudden fever accompanied by sore throat or mouth sores or disturbances in urination; methotrexate may cause acute reduction in the number of certain white blood cells (agranulocytosis) and severe bone marrow suppression [very rare]
• unexpected bleeding, e.g. bleeding gums, blood in urine, in vomit, or appearance of petechiae (small red or purple spots caused by bleeding under the skin); these may be symptoms of significant reduction in platelet count due to severe bone marrow suppression [very rare]
• symptoms such as severe headache often accompanied by fever, neck stiffness, nausea, vomiting, disorientation, and photophobia may indicate inflammation of the meninges (acute aseptic meningitis) [very rare]
• in cancer patients treated with methotrexate, certain brain disorders (encephalopathy / leukoencephalopathy) have been reported. Such adverse effects cannot be excluded when methotrexate treatment is used for other diseases. Symptoms of such brain disorders may include: altered mental status, motor disturbances (ataxia), visual disturbances or memory disturbances [frequency not known]
• severe skin rash or blisters on the skin (may also occur in the mouth, eyes, and genital organs); these may be symptoms of conditions known as Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell's syndrome) [very rare]

Below are other adverse effects that may occur:
Very common: may affect more than 1 in 10 people

• inflammation of the mucous membrane of the mouth, indigestion, nausea, loss of appetite, abdominal pain
• abnormal liver function tests (increased activity of AST, ALT, alkaline phosphatase, and increased bilirubin concentration)

Common: may affect up to 1 in 10 people

• ulceration of the mucous membrane of the mouth, diarrhea
• rash, skin redness, itching
• headache, fatigue, somnolence
• reduced blood cell production leading to decreased number of white and/or red blood cells and/or platelets

Uncommon: may affect up to 1 in 100 people

• sore throat
• enteritis, vomiting, pancreatitis, black or tarry stools, gastrointestinal ulceration and bleeding
• sunburn-like reactions due to increased skin sensitivity to sunlight, hair loss, increase in number of rheumatoid nodules, skin ulcers, herpes zoster, vasculitis, herpes-like rash, urticaria
• onset of diabetes
• dizziness, confusion, depression
• decreased albumin concentration in plasma
• decreased number of all types of blood cells, including platelets
• inflammation and ulceration of the bladder or vagina, kidney dysfunction, disturbances in urination
• joint pain, muscle pain, decreased bone mass

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

• gingivitis
• increased skin pigmentation, acne, blue spots on the skin due to bleeding from blood vessels (purpura, petechiae)
• allergic vasculitis
• decreased concentration of antibodies in blood
• infection (including reactivation of inactive chronic infection), conjunctivitis
• mood changes
• visual disturbances
• pericarditis, fluid accumulation in the pericardium, impaired heart filling due to fluid accumulation in the pericardium
• low blood pressure
• scar tissue formation in the lungs (pulmonary fibrosis), dyspnea and bronchial asthma, fluid accumulation in the pleura
• stress fractures
• electrolyte disturbances
• fever
• impaired wound healing

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

• severe bleeding, acute toxic megacolon (toxic dilation of the colon)
• increased nail pigmentation, inflammation of the nail fold (acute paronychia), deep infection of hair follicles (furunculosis), visible enlargement of small blood vessels
• local tissue damage (formation of sterile abscess, changes in fatty tissue) at the injection site
• pain, loss of muscle strength, or numbness or tingling sensation, reduced response to stimuli, taste disturbances (metallic taste), seizures, paralysis, meningeal reaction
• impaired vision, non-inflammatory eye disease (retinopathy)
• decreased libido, impotence, gynecomastia in men, disturbances in sperm production (oligospermia), menstrual disorders, vaginal discharge
• enlarged lymph nodes (lymphoma)
• lymphoproliferative disorders (overproduction of white blood cells)

Frequency not known: cannot be estimated from available data

• increased number of certain white blood cells
• nosebleeds
• proteinuria
• feeling of weakness
• pulmonary hemorrhage
• jaw bone damage (due to overproduction of white blood cells)
• tissue necrosis at the injection site
• redness and peeling of the skin
• swelling

Subcutaneously administered doses of methotrexate are locally well tolerated. Only mild local skin reactions (such as burning sensation, erythema, swelling, discoloration, itching, intense itching, pain) decreasing during treatment have been observed.
Reporting of adverse effects
If any adverse effects occur, including those not listed in this leaflet, you should inform your doctor or pharmacist. Adverse 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
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse effects can also be reported to the marketing authorization holder.
By reporting adverse effects, more information on the safety of the medicine can be collected.

5. How to store Methofill

Keep this medicine out of sight and reach of children.
Store below 30°C.
Keep the pre-filled syringes in the outer packaging to protect from light.
Do not use this medicine after the expiry date stated on the label/carton following EXP.
The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Package contents and other information

What Methofill contains

• The active substance is methotrexate. 1 ml of solution contains methotrexate disodium equivalent to 50 mg of methotrexate.
• Other ingredients are: sodium chloride, sodium hydroxide (for pH adjustment), and water for injections.

What Methofill looks like and contents of the pack
Methofill in pre-filled syringe ampoules is a clear, yellow to brown solution.
The pre-filled syringe ampoule is equipped with an additional needle safety shield. The packages contain pre-filled syringe ampoules available in blister packs with alcohol swabs. The blister packs are intended for single pre-filled syringe ampoules with an attached needle safety shield.
The following pack sizes are available:
Pre-filled syringe ampoules containing 0.15 ml, 0.20 ml, 0.30 ml, and 0.40 ml of solution are available in packs containing 1, 2, 4, 5, 6, 8, 10, 12, or 24 pre-filled syringe ampoules with attached needles with needle shield. The pre-filled syringe ampoule has an additional needle safety shield.
Pre-filled syringe ampoules containing 0.25 ml, 0.35 ml, 0.45 ml, 0.55 ml, and 0.60 ml of solution are available in packs containing 1, 4, 5, 6, 8, or 12 pre-filled syringe ampoules with attached needles with needle shield. The pre-filled syringe ampoule has an additional needle safety shield.
Pre-filled syringe ampoules containing 0.50 ml of solution are available in packs containing 1, 2, 4, 5, 6, 8, 10, or 12 pre-filled syringe ampoules with attached needles with needle shield. The pre-filled syringe ampoule has an additional needle safety shield.
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
Accord Healthcare Polska Sp. z o.o.
Lutomierska Street 50
95-200 Pabianice

This medicinal product is authorised in the European Economic Area countries and the United Kingdom (Northern Ireland) under the following names:

Instructions for Use
Before starting the injection, carefully read the instructions provided below.
Always follow the injection technique recommended by your doctor, pharmacist, or nurse.
If you have any problems or questions, consult your doctor, pharmacist, or nurse.

Preparation
Choose a well-lit, clean, and flat working surface.
Before starting, prepare the necessary items:

• 1 pre-filled syringe of Methofill with needle safety shield.

Wash hands thoroughly. Before use, inspect the Methofill pre-filled syringe for any visible
damage (or cracks).

Recommended injection sites include:

• the upper thigh,
• the abdomen, excluding the area around the navel.
  • If another person is assisting the patient with the injection, it may also be administered into the back of the upper arm.
  • Always select a different injection site each time. This helps reduce the risk of irritation at the injection site.
  • Never inject the medicine into areas that are painful, bruised, red, hardened, scarred, or have stretch marks. In patients with psoriasis, do not inject directly into raised, thickened, red, or scaly skin areas or lesions.

1. Solution Injection

Remove the pre-filled syringe with needle safety shield containing methotrexate from the packaging and carefully read the package leaflet.
The pre-filled syringe with needle safety shield should be removed from the packaging at room temperature.

2. Disinfection

Select the injection site and disinfect it with an alcohol swab.
Wait at least 60 seconds for the disinfectant to dry completely.

3. Check whether the pre-filled syringe mechanism is damaged

Do not use the product:

• if any damage is visible (e.g., broken syringe or broken needle safety shield) or if any components are missing.
• if the needle safety shield is already in the safety position before use, as shown in Fig. 7, indicating prior use. The product should not be used if the appearance of the pre-filled syringe does not match Fig. 3. In such cases, dispose of the product in a designated sharps container.

4. Remove the plastic protective cap

Hold the pre-filled syringe by the needle safety shield with the needle pointing away from you,
without touching the plunger.
With the other hand, remove the needle cap and dispose of it in a sharps container.

5. Inserting the needle

Gently pinch the skin at the injection site with one hand. With the other hand, without touching the plunger, insert the needle into the skin at a 90-degree angle.

6. Injection

Using your thumb, press the plunger rod steadily and inject the solution in a smooth motion.
Keep the skin fold held firmly until the injection is complete.

7. Needle safety mechanism activation

The safety mechanism activates when the plunger is fully depressed.
While holding the syringe, release pressure on the plunger and slowly lift your thumb.
The plunger will move upward with your thumb, and a spring will retract the needle, which is automatically covered by the shield.

8. Disposal of the safety shield

After use, dispose of the remaining shield with the attached needle into a sharps container.
Do not dispose of it in a regular waste bin.

Methotrexate must not come into contact with the skin or mucous membranes.
In case of contact, immediately rinse the affected area thoroughly with plenty of water.

Disposal and Handling Instructions
Disposal and handling of the medicine and pre-filled syringe must comply with local regulations.
Pregnant healthcare personnel should not prepare and/or administer Methofill.