Metother

Package leaflet: Information for the user

Metother 50 mg/ml injection solution in pre-filled syringe

methotrexate
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4. Contents of this leaflet:
  1. What Metother is and what it is used for
  2. What you need to know before using Metother
  3. How to use Metother
  4. Possible side effects
  5. How to store Metother
  6. Contents of the pack and other information

1. What Metother is and what it is used for

Metother contains the active substance methotrexate.
Methotrexate is a substance with the following properties:

• interferes with the growth of certain rapidly dividing cells in the body
• reduces the activity of the immune system (the body's defence mechanism)
• has anti-inflammatory effects

Metother is indicated for the treatment of:

• active rheumatoid arthritis in adult patients.
• severe active polyarticular juvenile idiopathic arthritis when the response to non-steroidal anti-inflammatory drugs (NSAIDs) has been inadequate.
• severe disabling psoriasis that is unresponsive and not adequately sensitive to other forms of therapy, such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients.
• mild to moderate Crohn's disease in adults when adequate treatment with other medications is not possible.

Rheumatoid arthritis (RA) is a chronic collagen disease characterized by inflammation of the synovial membranes (joint membranes). These membranes produce a fluid that acts as a lubricant for many joints. Inflammation causes thickening of the membrane and joint swelling. Juvenile arthritis affects children and adolescents under 16 years of age. When five or more joints are affected within the first 6 months of the disease, it is classified as polyarticular form.

Psoriatic arthritis is a type of arthritis associated with psoriatic skin and nail lesions, particularly affecting the joints of the fingers and toes.
Psoriasis is a common chronic skin disease characterized by red patches covered with dry, thick, silvery scales that are firmly attached and difficult to remove.
Metother 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. What you need to know before using Metother

Do not use Metother if:

• you are allergic to methotrexate or to any of the other ingredients of this medicine (listed in section 6)
• you have severe liver or kidney disease or blood disorders
• you regularly consume large amounts of alcohol
• you have serious infections, for example tuberculosis, HIV or other immunodeficiency syndromes
• you have mouth and throat ulcers or stomach and intestinal ulcers
• you are receiving vaccinations with live vaccines at the same time
• you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”)

Warnings and precautions
Tell your doctor, pharmacist or nurse before taking Metother if:

• you are elderly or have general malaise and weakness
• you have impaired liver function
• you suffer from dehydration (loss of fluids)

Cases of acute pulmonary hemorrhage have been reported in patients with rheumatological disease treated with methotrexate. If you notice blood in your saliva or after coughing, contact your doctor immediately.

Special precautionary measures for treatment with Metother
Methotrexate temporarily affects sperm and egg cell production, an effect which in most cases is reversible. Methotrexate may cause miscarriage and severe birth defects. While using methotrexate and for at least six months after stopping treatment, you must avoid pregnancy. See also section “Pregnancy, breastfeeding and fertility”.

Recommended follow-up tests and precautions:
Serious adverse effects may occur even when Methoter is used at low doses. To detect them early, your doctor must prescribe laboratory tests and check-ups.

Before starting treatment:
Before starting treatment, your doctor may request blood tests to check that blood cells are sufficient, assess proper liver function, serum albumin (a blood protein), and kidney function. Your doctor will also check whether you have tuberculosis (an infectious disease associated with small nodules in affected tissue), and a chest X-ray will be performed.

During treatment:
You will undergo the following tests at least once a month during the first six months and every three months thereafter:

• Examination of mouth and throat for mucosal changes
• Blood tests
• Liver function monitoring
• Kidney function monitoring
• Respiratory tract examination and, if necessary, lung function tests

Methotrexate may affect the immune system and vaccination outcomes. It may also influence the results of immunological tests. Chronic latent infections (e.g., herpes zoster [shingles], tuberculosis, hepatitis B or C) may reactivate. During treatment with Metother, you must not be vaccinated with live vaccines.

Radiation-induced dermatitis and sunburns may reappear during methotrexate therapy (recall reaction). Psoriatic lesions may worsen during UV irradiation and concurrent administration of methotrexate.

Enlargement of lymph nodes (lymphoma) may occur, and therefore treatment should be discontinued.

Diarrhea may be a toxic effect of Metother and may require discontinuation of therapy. If you experience diarrhea, inform your doctor.

Encephalopathy (a brain disorder)/leukoencephalopathy (a specific disorder of the brain's white matter) have been reported in oncology patients treated with methotrexate, and other pathologies following methotrexate therapy cannot be excluded.

Other medicines and Metother
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The treatment effect may be compromised if Metother is administered simultaneously with certain other drugs:

• Medicines that damage the liver or blood count, for example, leflunomide
• Antibiotics (medicines to prevent/treat certain infections), such as: tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics, penicillins, glycopeptides, sulfonamides (sulfur-containing drugs that prevent/treat certain infections), ciprofloxacin and cephalothin
• Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or inflammation)
• Probenecid (a medicine for gout)
• Weak organic acids, such as loop diuretics ("water tablets") or certain medicines used to treat inflammatory diseases and pain (e.g., acetylsalicylic acid, diclofenac and ibuprofen) and pyrazoles (e.g., metamizole for pain treatment)
• Medicines that may have negative effects on bone marrow, for example, trimethoprim-sulfamethoxazole (an antibiotic) and pyrimethamine
• Sulfasalazine (an anti-rheumatic medicine)
• Azathioprine (an immunosuppressive agent sometimes used in severe forms of rheumatoid arthritis)
• Mercaptopurine (a cytostatic agent)
• Retinoids (medicines for psoriasis and other dermatological diseases)
• Theophylline (a medicine for bronchial asthma and other lung diseases)
• Proton pump inhibitors (medicines for gastric disorders, such as omeprazole and pantoprazole)
• Hypoglycemics (medicines used to lower blood glucose)

Vitamins containing folic acid may reduce the treatment effect and should only be taken if recommended by your doctor.

Vaccination with live vaccines must be avoided.

Metother with food, drinks and alcohol
During treatment with Metother, excessive alcohol consumption as well as large quantities of coffee, caffeine-containing non-alcoholic beverages and black tea should be avoided.

Pregnancy, breastfeeding and fertility
Pregnancy
Do not use Metother during pregnancy or if you are trying to become pregnant. Methotrexate may cause birth defects, harm the fetus or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain and limbs. Therefore, it is very important that pregnant women or women planning a pregnancy are not treated with methotrexate. In women of childbearing age, any possibility of pregnancy must be ruled out using appropriate measures, for example by performing a pregnancy test before starting treatment. You must avoid pregnancy by using reliable contraceptive methods throughout the entire period of taking methotrexate and for at least 6 months after stopping treatment (see also section “Warnings and precautions”).

If you become pregnant during treatment or suspect you are pregnant, contact your doctor as soon as possible. You will receive counseling regarding the risk of harmful effects on the baby due to the treatment.

If you plan a pregnancy, you should consult your doctor, who will refer you to a specialist before the intended start of treatment.

Male fertility
Available evidence does not indicate an increased risk of birth defects or miscarriage if the father takes a methotrexate dose below 30 mg/week. However, the risk cannot be completely excluded. Methotrexate may be genotoxic. This means that the medicine may cause genetic mutations. Methotrexate may affect sperm production and potentially cause birth defects. Therefore, while taking methotrexate and for at least 6 months after stopping treatment, you should avoid fathering a child or donating semen.

Breastfeeding must be discontinued before and during treatment with Metother.

Driving and use of machines
Treatment with Metother may cause adverse reactions affecting the central nervous system, for example fatigue and dizziness. Therefore, in some cases your ability to drive a vehicle and/or operate machinery may be impaired. If you feel tired or experience drowsiness, you must not drive or operate machinery.

Metother contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per dose, i.e., it is essentially "sodium-free".

3. How to use Metother

The doctor will determine the dosage, which will be individually adjusted. Usually, 4-8 weeks are necessary before any treatment effect becomes apparent.
Metother is administered as a subcutaneous injection (under the skin) by or under the supervision of a doctor or healthcare professional only once a week. Together with your doctor, choose a suitable weekday on which to receive the injection every week.
Important warning regarding the dosage of Metother (methotrexate):
In the treatment of Rheumatoid Arthritis, Juvenile Arthritis, Psoriatic Arthritis, Psoriasis, Crohn's Disease,
Metother (methotrexate) must be taken only once a week. Overuse of Metother (methotrexate) can be fatal. Read paragraph 3 of this leaflet very carefully. In case of doubt, consult your doctor or pharmacist before taking this medicine.
Use in children and adolescents
The doctor will determine the appropriate dose for children and adolescents with polyarticular forms of juvenile idiopathic arthritis.
Metother is not recommended in children under 3 years of age due to limited experience in this age group.
Method and duration of administration
Metother is injected only once a week!
The duration of treatment is determined by the treating doctor. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis, and Crohn's disease with Metother is a long-term treatment.
At the beginning of treatment, Metother will be administered by medical staff. However, your doctor may consider that you are able to learn how to self-administer Metother injections. In this case, you will receive appropriate training. Under no circumstances should you attempt to self-inject without having received adequate training. Please refer to the instructions for use at the end of this leaflet.
Please ensure that the entire content is used.
Handling and disposal must be consistent with that of other cytostatic agents, in accordance with current local regulations. Healthcare personnel who are pregnant must not handle and/or administer Metother.
Methotrexate must not come into contact with the surface of the skin or mucous membranes. In case of contamination, immediately wash the affected area thoroughly with plenty of water.
If you use more Metother than you should
If you use more Metother than prescribed, contact your doctor immediately.
If you forget to use Metother
Do not take a double dose to make up for the forgotten dose.
If you stop using Metother
If you stop using Metother, contact your doctor immediately.
If you feel that the effect of Metother is too strong or too weak, inform your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The frequency and severity of side effects depend on the type of dosage and frequency of administration. Since serious side effects may occur even at low doses, it is important to be regularly monitored by your doctor. Your doctor will prescribe tests to monitor for emerging abnormalities in the blood (such as reduced number of white blood cells, low platelets, lymphoma) and changes in the kidneys and liver.
Contact your doctor immediately if you experience any of the following symptoms, as these may indicate a serious, potentially life-threatening adverse reaction requiring specific treatment:

• Persistent, dry, non-productive cough, shortness of breath, and fever; these may be signs of lung inflammation [common – may affect up to 1 in 10 people]
• Blood in saliva or after coughing
• Signs of liver damage, such as yellowing of the skin and whites of the eyes; methotrexate may cause chronic liver damage (liver cirrhosis), scarring of liver tissue (liver fibrosis), fatty degeneration of the liver [all uncommon – may affect up to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare – may affect up to 1 in 1,000 people], and liver failure [very rare – may affect up to 1 in 10,000 people]
• Signs of allergy such as skin rashes including redness and itching of the skin, swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), and feeling faint; these may be signs of severe allergic reactions or anaphylactic shock [rare – may affect up to 1 in 1,000 people]
• Signs of kidney damage, such as swelling of the hands, ankles or feet, or changes in frequency of urination, or reduced (oliguria) or absent (anuria) urine output; these may be signs of kidney failure [rare – may affect up to 1 in 1,000 people]
• Signs of infection, e.g. fever, chills, tenderness, sore throat; methotrexate may increase susceptibility to infections. Rarely [may affect up to 1 in 1,000 people], severe infections such as a certain type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis) may occur
• Symptoms such as weakness on one side of the body (stroke) or pain, swelling, redness and unusual warmth in a leg (deep vein thrombosis); this may occur when a blood clot blocks a blood vessel (thromboembolic event) [rare – may affect up to 1 in 1,000 people]
• Symptoms such as fever and severe worsening of general condition, or sudden fever accompanied by sore throat or mouth pain, or urinary problems; methotrexate may very rarely [may affect up to 1 in 10,000 people] cause a severe drop in certain white blood cells (agranulocytosis) and severe bone marrow suppression
• Unexpected bleeding, e.g. bleeding gums, blood in urine, vomiting blood, or bruising; these may be signs of a severe reduction in platelet count due to serious bone marrow depression [very rare – may affect up to 1 in 10,000 people]
• Symptoms such as severe headache, often combined with fever, neck stiffness, nausea, vomiting, disorientation, and sensitivity to light; these may indicate inflammation of the membranes surrounding the brain (acute aseptic meningitis) [very rare – may affect up to 1 in 10,000 people]
• Some brain disorders (encephalopathy/leukoencephalopathy) have been reported in cancer patients treated with methotrexate. Such adverse effects cannot be excluded when methotrexate therapy is used to treat other diseases. Signs of such brain disorders may include altered mental status, movement disorders (ataxia), visual disturbances, or memory problems [not known: frequency cannot be estimated from available data]
• Severe skin rash or blistering of the skin (may also affect the mouth, eyes and genitals); these may be signs of a very rare condition [may affect up to 1 in 10,000 people] called Stevens-Johnson syndrome or "burned skin" syndrome (toxic epidermal necrolysis/Lyell's syndrome)

The following are other side effects that may occur:

Very common: may affect more than 1 in 10 people

• Inflammation of the lining of the mouth, indigestion, malaise, loss of appetite, abdominal pain.
• Abnormal liver function tests (ASAT, ALAT, bilirubin, alkaline phosphatase).

Common: may affect up to 1 in 10 people

• Mouth ulcers, diarrhoea
• Skin rash, skin redness and itching
• Headache, fatigue, drowsiness
• Reduced production of blood cells with decrease in white and/or red blood cells and/or platelets

Uncommon: may affect up to 1 in 100 people

• Sore throat
• Inflammation of the intestine, vomiting, inflammation of the pancreas, black tarry stools, gastrointestinal ulcers and bleeding
• Increased sensitivity to light, hair loss, increase in number of rheumatoid nodules, skin ulcer, shingles (herpes zoster), inflammation of blood vessels, herpes-like skin rashes, hives
• Onset of diabetes mellitus
• Dizziness, confusion, depression
• Decrease in serum albumin
• Reduction in number of all blood cells and platelets
• Inflammation and ulceration of the urinary bladder or vagina, reduced kidney function, urinary disorders
• Joint pain, muscle pain, reduced bone mass

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

• Inflammation of the gum tissue
• Increased skin pigmentation, acne, bruising due to bleeding from blood vessels (ecchymoses, petechiae)
• Allergic inflammation of blood vessels
• Reduction in number of antibodies in the blood
• Infection (including reactivation of a previously inactive chronic infection), red eyes (conjunctivitis)
• Mood swings (mood changes)
• Visual disturbances
• Inflammation of the sac around the heart, fluid accumulation in the sac around the heart, obstruction of heart filling due to fluid in the sac around the heart
• Low blood pressure
• Scarring of lung tissue (pulmonary fibrosis), shortness of breath and bronchial asthma, fluid accumulation in the sac around the lung
• Stress fracture
• Electrolyte disturbances
• Fever, impaired wound healing

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

• Acute toxic dilation of the intestine (toxic megacolon)
• Increased nail pigmentation, inflammation of the nail folds (acute paronychia), deep infection of hair follicles (furunculosis), visible dilation of small blood vessels
• Pain, loss of strength, or numbness, tingling/less sensitivity than normal to stimulation, taste disturbances (metallic taste), seizures, paralysis, meningism
• Visual disturbances, non-inflammatory eye disease (retinopathy)
• Loss of sexual desire, impotence, breast enlargement in males, formation of defective sperm (oligospermia), menstrual disorders, vaginal discharge
• Enlargement of lymph nodes (lymphoma)
• Lymphoproliferative disorders (excessive growth of white blood cells)

Not known: frequency cannot be estimated from available data:

• Increase in number of certain white blood cells
• Nosebleeds
• Protein in urine
• Feeling of weakness
• Bleeding from the lungs
• Bone damage in the jaw/mandible (secondary to excessive growth of white blood cells)
• Tissue destruction at injection site
• Skin redness and peeling
• Swelling

Subcutaneous administration of methotrexate is well tolerated locally. Only mild local skin reactions (such as burning sensation, erythema, swelling, discoloration, intense itching, pain) have been observed, which tend to diminish during treatment.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Metother

Keep this medicine out of the sight and reach of children.
Store below 30°C.
Keep the pre-filled syringes in the outer packaging to protect them from light.
Do not use this medicine after the expiry date stated on the label/carton after Exp. The expiry date refers to the last day of that month.
Do not use Metother if you notice any signs of colour change or if it contains visible particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Metother contains

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

Description of the appearance of Metother and contents of the pack
Metother pre-filled syringe contains a clear solution ranging from yellow to brown. The pre-filled syringes
are pre-attached with a safety needle. The packs containing the pre-filled syringes are available with or without
blister packs and alcohol-impregnated swabs. The blisters are for single pre-filled syringes pre-attached with a safety needle.
The following pack sizes are available:

• For 0.15 ml, 0.20 ml, 0.30 ml and 0.40 ml: packs containing 1, 2, 4, 5, 6, 8, 10, 12 and 24 pre-filled syringes with fixed needle covered with a rigid cap. Additional pre-filled syringes pre-attached with a safety needle.
• For 0.25 ml, 0.35 ml, 0.45 ml, 0.55 ml and 0.60 ml: packs containing 1, 4, 5, 6, 8 and 12 pre-filled syringes with fixed needle covered with a rigid cap. Additional pre-filled syringes pre-attached with a safety needle.
• For 0.50 ml: packs containing 1, 2, 4, 5, 6, 8, 10 and 12 pre-filled syringes with fixed needle covered with a rigid cap. Additional pre-filled syringes pre-attached with a safety needle. Not all pack sizes may be marketed.

Marketing Authorisation Holder
Accord Healthcare S.L.U.
World Trade Center,
Moll de Barcelona,
s/n, Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer
Accord Healthcare Limited
Ground Floor, Sage House, 319 Pinner Road, Harrow, Middlesex,
HA1 4HF
United Kingdom
Wessling Hungary Kft
Fòti ùt 56., Budapest
Hungary

This medicinal product is authorised in the Member States of the European Economic Area under the following names:

Instructions for use
Read the following instructions carefully before starting the injection and always use the injection technique recommended by your doctor, pharmacist or nurse.
For any problems or questions, consult your doctor, pharmacist or nurse.

Preparation
Select a clean, well-lit, flat surface.
Gather all necessary items before starting:

• 1 pre-filled syringe of Metother with safety needle
  Wash hands thoroughly. Before use, inspect the Metother syringe for any defects (or cracks).

Injection site
The most appropriate sites for injection are:

• upper thighs,
• abdomen, except around the navel.

• If someone is assisting you with the injection, they may also administer the injection in the back of the upper arms, just below the shoulder.
• Change the injection site with each injection. This can reduce the risk of developing injection site reactions.
• Do not inject into skin that is tender, bruised, red, hard, scarred, or where you have stretch marks. If you have psoriasis, try not to inject directly into any raised, thick, red or scaly patches or lesions.

Injecting the solution

1. Open the pre-filled syringe with attached safety needle and read the package leaflet carefully. Remove the pre-filled syringe with attached safety needle from its packaging at room temperature.
2. Disinfection

Choose an injection site and disinfect it with an
alcohol swab. Wait at least 60 seconds to allow the
disinfectant to dry.

3. Ensure the system is intact/undamaged

Do not use the product:

• If you notice damage (breakage of the syringe or safety needle) or loss of components;
• If the safety needle is in the safety position before use as shown in Figure 7, because this indicates that the system has already been used. In general, the product should not be used if it does not match the image on the left-hand side. In such cases, dispose of the product in appropriate containers for sharps (sharp objects) with biological risk.

4. Remove the protective cap

• Hold the safety needle barrel in one hand

with the needle pointing away from you and without touching the plunger;

• Remove the needle cap straight off with the other hand;
• After removal, discard the needle cap into an appropriate container for sharps (sharp objects) with biological risk.

5. Insert the needle

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

6. Injection

• Place your thumb on the plunger head;

• Press the plunger and push firmly until the injection is complete to ensure the syringe is fully emptied. Hold the skin firmly until the injection is finished.

7. Plunger shield protection

The safety mechanism will activate once the
plunger is fully depressed:

• Keep holding the syringe and slowly lift your thumb from the piston head;
• The piston rod will move with your thumb and the spring will retract the needle from the site into the needle safety shield.

8. Disposal of the safety needle

Once the syringe has been used, immediately dispose of the safety needle device into appropriate containers for sharps (sharp objects) with

Methotrexate must not come into contact with the skin or mucosal surface. In case of contamination, immediately wash the affected area thoroughly with abundant water.
If you or someone near you is injured by the needle, seek immediate medical advice and do not use this pre-filled syringe.

Use and handling
Handling and disposal of the medicinal product and pre-filled syringe must comply with the regulations for other cytotoxic preparations, in accordance with local regulations. Healthcare personnel who are pregnant must not handle and/or administer Metother.