Package leaflet: Information for the user

Metotrexato Aurobindo 2.5 mg tablets

Equivalent medicine
Please read this leaflet carefully before taking 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 or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

What Metotrexato Aurobindo is and what it is used for
What you need to know before taking Metotrexato Aurobindo
How to take Metotrexato Aurobindo
Possible side effects
How to store Metotrexato Aurobindo
Contents of the pack and other information

1. What Metotrexato Aurobindo is and what it is used for

The active substance of Metotrexato Aurobindo, methotrexate, is a compound with the following properties:

suppresses the growth of certain rapidly dividing cells in the body;
reduces the activity of the immune system (the body's defence mechanism).

Methotrexate is used in the treatment of:

active rheumatoid arthritis in adults;
juvenile arthritis in children aged 3 years and above and in adolescents (severe active juvenile idiopathic arthritis), when five or more joints are involved and response to treatment with another class of medicines (so-called non-steroidal anti-inflammatory drugs (NSAIDs)) is inadequate;
severe, recurrent, disabling psoriasis in adults, which does not respond adequately to other forms of therapy such as phototherapy, PUVA, and retinoids;
severe psoriatic arthritis in adults;
maintenance therapy of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children aged 3 years and above.

Your doctor will be able to explain how Metotrexato Aurobindo could help in your specific situation.

2. What you should know before taking Metotrexato Aurobindo

Do not take Metotrexato Aurobindo

if you are allergic (hypersensitive) to methotrexate or to any of the other ingredients of this medicine (listed in section 6);
if you are breastfeeding and, additionally, for non-oncological indications (for non-anticancer treatments), if you are pregnant (see section “Pregnancy, breastfeeding and fertility”);
if you have severe liver or kidney disease (your doctor will assess the severity of the condition);
if you have or have had bone marrow disease or severe blood disorders;
if you have severe acute or chronic infections;
if you have immunodeficiency syndrome;
if you have inflammation of the mouth mucosa or mouth ulcers;
if you have stomach or intestinal ulcers;
if you suffer from alcoholism;
if you have recently received or are about to receive a vaccination with live vaccines.

Warnings and precautions
Important warning about the dosage of Metotrexato Aurobindo (methotrexate):
Take Metotrexato Aurobindo only once a week for the treatment of rheumatoid arthritis, acute lymphoblastic leukemia, psoriasis or psoriatic arthritis, juvenile idiopathic arthritis ( juvenile idiopathic arthritis, JIA). An overdose of Metotrexato Aurobindo (methotrexate) can be fatal. Please read carefully section 3 of this leaflet. If you have any doubts, consult your doctor or pharmacist before taking this medicine.
Contact your doctor, pharmacist or nurse before taking Metotrexato Aurobindo:

if you have ever had any liver or kidney disease;
if you suffer from inactive chronic infections (e.g. tuberculosis, hepatitis B or C, herpes zoster), as they may reactivate;
if your general health condition is poor;
if you have lung function problems;
if you are significantly overweight;
if you have abnormal fluid accumulation in the abdomen (ascites) or around the lungs (pleural effusions);
if you have diabetes mellitus and are being treated with insulin;
if you are dehydrated or suffer from conditions causing dehydration (vomiting, diarrhea, constipation, inflammation of the mouth mucosa).

Cases of acute pulmonary hemorrhage have been reported in patients with rheumatic disease treated with methotrexate. If you notice symptoms such as blood in saliva or after coughing, contact your doctor immediately.
Diarrhea may be a possible side effect of Metotrexato Aurobindo and requires discontinuation of therapy. If you experience diarrhea, please consult your doctor.
Methotrexate temporarily affects sperm and egg cell production. Methotrexate may cause miscarriage and serious birth defects. If you are a woman, you must avoid becoming pregnant during treatment with methotrexate and for at least six months after the end of treatment with methotrexate. If you are a man, you must avoid fathering a child during treatment with methotrexate and for at least 3 months after the end of treatment. See section “Pregnancy, breastfeeding and fertility”.
Methotrexate may make your skin more sensitive to sunlight. Avoid exposure to strong sunlight and do not use sunbeds or tanning lamps without medical advice. To protect your skin from intense sunlight, wear appropriate clothing or use sunscreen with a high protection factor.
Radiation therapy during treatment with Metotrexato Aurobindo may increase the risk of soft tissue necrosis or bone necrosis. If you have had skin problems after radiation therapy (radiation dermatitis) or sunburns, these reactions may reappear during treatment with methotrexate (“radiation recall reaction”). Skin changes due to psoriasis may worsen during methotrexate treatment if exposed to UV rays.
Probenecid reduces renal tubular transport; therefore, concomitant administration of methotrexate with this medicine must be closely monitored. Probenecid and weak organic acids such as pyrazoles reduce methotrexate elimination, resulting in increased hematological toxicity.
Enlarged lymph nodes (lymphoma) may occur in patients treated with low-dose methotrexate; in such cases, treatment should be discontinued.
If you, your partner or caregiver notice the onset or worsening of neurological symptoms, including general muscle weakness, vision disturbances, changes in thinking, memory and orientation leading to confusion and personality changes, contact your doctor immediately, as these may be symptoms of a very rare and serious brain infection called progressive multifocal leukoencephalopathy ( progressive multifocal leukoencephalopathy, PML).
Other brain disorders (encephalopathy/leukoencephalopathy) have been reported in oncology patients treated with methotrexate. These side effects cannot be excluded when methotrexate is used to treat other diseases.

Recommended monitoring tests and precautions
Even when methotrexate is used at low doses, serious side effects may occur. To detect them early, your doctor must perform monitoring tests and laboratory analyses.

Before starting treatment:
Before starting treatment, your blood will be tested to ensure you have an adequate number of blood cells. Your blood will also be analyzed to check liver function and to detect whether you have hepatitis. Additionally, serum albumin (a protein in the blood), possible hepatitis status (liver infection), and kidney function will be checked. Your doctor may also decide to perform additional liver tests, some of which may involve imaging of your liver, while others may require taking a small tissue sample from the liver for closer examination. Your doctor may also check whether you have tuberculosis and may perform a chest X-ray or lung function test.

During treatment:
Your doctor may perform the following tests:

examination of the oral cavity and pharynx to detect mucosal changes such as inflammation or ulceration;
blood tests / blood cell count and measurement of serum methotrexate levels;
blood tests to monitor liver function;
imaging to monitor liver condition;
taking a small tissue sample from the liver for closer examination;
blood tests to monitor kidney function;
monitoring of the respiratory tract and, if necessary, lung function tests.

It is very important that you attend these scheduled tests. If any of these test results are significant, your doctor will adjust your treatment accordingly.

Children, adolescents and elderly
Children, adolescents and elderly patients (65 years of age and older) treated with methotrexate must be closely monitored by a doctor to detect any side effects as early as possible.
Age-related impairment of liver and kidney function, as well as reduced body stores of folic acid in older age, require a relatively low dosage of methotrexate.
Use in children under 3 years of age is not recommended due to insufficient experience in this age group.

Other medicines and Metotrexato Aurobindo
Taking other medicines concomitantly may affect the efficacy and safety of this medicine. Metotrexato Aurobindo may also affect the efficacy and safety of other medicines.
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Remember to inform your doctor about treatment with Metotrexato Aurobindo if you are prescribed another medicine while treatment is ongoing. It is particularly important to inform your doctor if you are taking:

metamizole (synonyms: novaminsulfon, dipyrone) (a medicine for severe pain and/or fever);
antibiotics (medicines to prevent/treat certain infections) such as penicillins, sulfonamides, ciprofloxacin, cephalothin, trimethoprim/sulfamethoxazole, tetracycline and chloramphenicol. For example, antibiotics such as amoxicillin may reduce methotrexate excretion, potentially increasing adverse reactions;
other medicines used to treat rheumatoid arthritis such as leflunomide, sulfasalazine and azathioprine;
certain pain and/or anti-inflammatory medicines known as non-steroidal anti-inflammatory drugs (e.g. ibuprofen, diclofenac, salicylates such as acetylsalicylic acid);
pyrimethamine (for prevention and treatment of malaria);
antineoplastic agents (e.g. mercaptopurine, 5-fluorouracil, doxorubicin, olaparib and procarbazine);
antiepileptic medicines (to prevent epileptic seizures);
omeprazole or pantoprazole (medicines used to suppress gastric acid production);
diuretics;
medicines to lower blood sugar levels such as metformin;
cholestyramine (a medicine that binds bile acids and may be used, for example, to lower cholesterol levels);
cyclosporine (a medicine that may suppress or prevent immune response);
retinoids (for treatment of psoriasis and other skin diseases);
oral contraceptives;
barbiturates (medicines for sleep);
sedatives;
nitrous oxide (used for general anesthesia);
probenecid (a medicine used for gout);
theophylline (a medicine used for respiratory diseases);
vitamin preparations or other products containing folic acid and derivatives;
live vaccines (see section 2 “Do not take Metotrexato Aurobindo”).

Metotrexato Aurobindo with food, drinks and alcohol
During treatment with Metotrexato Aurobindo, alcohol consumption must be avoided, as well as large amounts of coffee, caffeinated soft drinks and black tea. Make sure you drink plenty of fluids during treatment with Metotrexato Aurobindo tablets, as dehydration (reduction of body fluids) may increase the side effects of methotrexate.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
Do not use Metotrexato Aurobindo during pregnancy unless your doctor has prescribed it as oncological treatment.
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 essential that methotrexate is not administered to pregnant women or women planning a pregnancy, except in oncological treatments.
For non-oncological indications, in women of childbearing potential, pregnancy must be ruled out before starting treatment, for example by performing a pregnancy test.
Do not use Metotrexato Aurobindo if you are trying to become pregnant. During treatment with methotrexate and for at least 6 months after the end of treatment, you must avoid becoming pregnant. Therefore, you must ensure you use an effective contraceptive method throughout this period (see also section “Warnings and precautions”).
If you become pregnant during treatment or suspect you may be pregnant, contact your doctor as soon as possible.
If you become pregnant during treatment, you will be advised about the risk of harmful effects on the fetus due to the treatment.
If you wish to become pregnant, you should discuss this with your doctor, who may refer you to a specialist before the planned start of treatment.

Breastfeeding
Do not breastfeed during treatment, as methotrexate passes into breast milk. If your doctor considers treatment with methotrexate absolutely necessary during breastfeeding, breastfeeding must be discontinued.

Male fertility
Available evidence does not indicate an increased risk of birth defects or miscarriage if the father takes methotrexate at a dose 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 a genotoxic effect. This means the drug may cause genetic mutations. Methotrexate may affect sperm production, possibly causing birth defects.
You must avoid fathering children or donating sperm during treatment with methotrexate and for at least 3 months after the end of treatment. Since treatment with higher doses of methotrexate, commonly used in cancer therapy, may cause infertility and genetic mutations, male patients treated with methotrexate doses exceeding 30 mg/week may be advised to consider sperm preservation before starting treatment (see also section “Warnings and precautions”).

Ask your doctor or pharmacist before taking any medicine.

Driving and using machines
During treatment with Metotrexato Aurobindo, you may experience fatigue and dizziness. Do not drive or operate machinery if you experience these symptoms.

3. How to take Metotrexato Aurobindo

Take this medicine exactly as directed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.

Patients with rheumatoid arthritis, acute lymphoblastic leukemia, psoriasis, psoriatic arthritis, or juvenile idiopathic arthritis (JIA) must take the tablets orally only once a week, on the same day each week.
Do not take the tablets more often than prescribed by your doctor.
Daily administration may lead to serious adverse effects, including death.
Take the tablets with a glass of water, while sitting or standing.

Dosage for rheumatoid arthritis
Take the tablets once a week, always on the same day of the week. The usual dose ranges from 7.5 to 20 mg once weekly.
Dosage for psoriasis and severe psoriatic arthritis
Take the tablets once a week, always on the same day of the week. The usual dose ranges from 7.5 to 15 mg once weekly.
Dosage for maintenance therapy in acute lymphoblastic leukemia
Take the tablet once a week, always on the same day of the week. Your doctor will calculate the required dose based on your body surface area. Your doctor will determine the correct dose for you. For further information, consult your doctor.
Dosage for juvenile idiopathic arthritis (JIA)
Take the tablet once a week, always on the same day of the week. The recommended initial dose is 10 mg/m² of body surface area per week, given as a single dose.

Special populations
In elderly patients and in patients with renal or hepatic impairment, a reduced dose is usually used as prescribed by the doctor. See also section 2 “Do not take Metotrexato Aurobindo”.

Use in children and adolescents
For children and adolescents receiving maintenance therapy for acute lymphoblastic leukemia, the doctor will individually calculate the required dose based on body surface area.

Safe handling of Metotrexato Aurobindo
Appropriate procedures for the safe handling of cytotoxic agents must be followed. Anyone handling methotrexate should wash their hands before and after administering a dose. Disposable gloves must be used when handling methotrexate tablets. Pregnant women, women planning pregnancy, or women who are breastfeeding should, if possible, avoid handling methotrexate tablets.
Contact with skin or mucous membranes must be avoided. In case of contact with skin or mucous membranes, wash immediately and thoroughly with soap and water.
Parents, caregivers, and patients should be advised to keep methotrexate out of the reach of children, preferably in a locked cabinet.
Accidental ingestion may be fatal in children.

If you take more Metotrexato Aurobindo than you should
If you take (or someone else has taken) more medicine than prescribed, contact your doctor or the nearest hospital emergency department immediately.
Taking an excessive dose of methotrexate may cause severe toxic reactions, including death. Symptoms of overdose may include tendency to bruise or bleed, unusual weakness, mouth ulcers, nausea, vomiting, black or bloody stools, coughing up blood or vomiting material resembling coffee grounds, and reduced urine output. See also section 4 “Possible side effects”.
Bring the medicine package with you when you go to the doctor or hospital. If you have taken an excessive dose of methotrexate, calcium folinate will be administered to reduce its adverse effects.

If you forget to take Metotrexato Aurobindo
Take the missed dose as soon as you remember, provided this occurs within two days. However, if you have forgotten a dose for more than two days, contact your doctor for advice. Do not take a double dose to make up for the missed dose.
Before going on holiday or traveling, ensure you have an adequate supply of medicine.

If you stop taking Metotrexato Aurobindo
Do not stop treatment with Metotrexato Aurobindo unless instructed by your doctor. If it becomes necessary to discontinue treatment with Metotrexato Aurobindo, your doctor will decide which method is most suitable for you.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. In general, the incidence and severity of adverse reactions to methotrexate are dose- and frequency-dependent. Most adverse reactions are reversible if detected early.
Contact your doctor immediately if you notice any of the following symptoms, as they may indicate a serious, potentially life-threatening adverse reaction requiring specific treatment:

Inflammation of the lungs (symptoms may include general malaise, dry and irritating cough, shortness of breath, breathlessness at rest, chest pain, or fever).
Blood in saliva or coughed up after coughing.
Unusual bleeding (including vomiting blood), bruising, or nosebleeds.
Nausea, vomiting, abdominal pain, or severe diarrhea.
Mouth ulcers.
Black or tarry stools.
Severe allergic reaction causing fever, skin rash, swelling, and sometimes low blood pressure. An extremely severe allergic reaction with skin rashes, commonly presenting as blisters or sores in the oral cavity, eyes, and other mucous membranes such as the genitals (Stevens-Johnson syndrome, toxic epidermal necrolysis – Lyell’s syndrome).
Any signs of infection, such as fever or a marked worsening of general health, or fever with local signs of infection such as sore throat/throat or mouth inflammation, or difficulty urinating; consult your doctor immediately. Methotrexate may reduce the number of white blood cells and thus weaken the immune defenses. A blood test will be performed to check for a reduction in white blood cells (agranulocytosis).
Yellowing of the skin (jaundice).
Pain or difficulty urinating.
Thirst and/or frequent urination.
Blurred or reduced vision.

Most of the effects listed below are observed only in patients treated with high doses of methotrexate for cancer treatment. They do not occur with the same frequency and severity at the doses used for the treatment of psoriasis or rheumatoid arthritis.
Very common (may affect more than 1 in 10 people)

Loss of appetite, feeling unwell (nausea), vomiting, indigestion, stomach ache, stomatitis (pain in mouth and lips).
Increased liver enzymes.
Macrocytosis.

Common (may affect up to 1 in 10 people)

Infections.
Reduced formation of blood cells with decreased white blood cells and/or red blood cells and/or platelets (leukopenia, anemia, thrombocytopenia).
Headache, dizziness, unusual tiredness, drowsiness.
Lung infection (pneumonia), dry cough.
Diarrhea.
Skin rash, redness of the skin, itching.
Alopecia.

Uncommon (may affect up to 1 in 100 people)

Cancer of the lymph nodes (or tissues).
Diabetes mellitus.
Depression, confusion.
Seizures, vertigo.
Gastrointestinal ulcers and bleeding.
Non-infectious peritonitis.
Glossitis.
Nosebleeds.
Excessive formation of fibrous connective tissue in an organ (fibrosis).
Decreased serum albumin levels.
Inflammation of blood vessels, often with skin rash (vasculitis), increased skin pigmentation, slow wound healing, increase in rheumatoid nodules.
Ulcers and inflammation of the bladder, urinary disorders.
Liver damage.
Joint or muscle pain, decreased bone mineral density, a type of bone disease (osteoporosis).
Vaginal inflammation and ulceration.
Chills.
Sunburn-like reactions due to increased skin sensitivity to sunlight.

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

Generalized inflammation with fatal outcome (sepsis), herpes zoster infection.
A blood disorder characterized by the appearance of very large red blood cells (megaloblastic anemia).
Mood changes.
Weakness in movement (also limited to the left or right side of the body).
Severe vision disturbances.
Fluid in the sac surrounding the heart. This may lead to cardiac tamponade, a potentially life-threatening condition in which the heart cannot pump properly due to external pressure. Medical intervention may be required to drain the fluid and relieve pressure.
Hypotension, thromboembolism.
Complete or severe weakness of respiratory muscles, shortness of breath, inflammation of the back of the throat, asthma.
Inflammation of the pancreas, inflamed gums.
Inflammation of the liver (acute hepatitis).
Skin reactions (acne, skin depigmentation, urticaria, erythema multiforme, burning sensation in psoriatic skin lesions, skin ulcers, red or purple spots due to bleeding from blood vessels), nail detachment, dark areas on the nails.
Stress fractures.
Reduced or absent urine production, electrolyte disturbances.
Menstrual disorders, impotence.

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

Immunodeficiency (hypogammaglobulinemia), increased susceptibility to infections.
Lymphoproliferative disorders (excessive growth of white blood cells).
Insomnia.
Brain swelling, difficulty speaking (dysarthria), irritability, drowsiness, fatigue (lethargy), mild temporary problems with intellectual functions ("mental clouding"),
unusual sensations in the head, muscle weakness, numbness or tingling/reduced sensitivity to stimuli compared to normal, changes in taste sensation (metallic taste).
Redness and irritation of the thin membrane covering the eye (conjunctivitis), visual impairment, retinal damage.
Inflammation of blood vessels (vasculitis), vomiting blood.
Reactivation of chronic liver inflammation, liver failure.
Colon enlargement associated with inflammation/infection.
Infection around a nail, deep infection of hair follicles (furunculosis), bruising, acne.
Presence of blood proteins in urine, painful urination, bladder inflammation.
Low sperm count, breast enlargement in men, vaginal bleeding, loss of libido.
Fever.
Sudden death.

The following adverse effects have also been reported, but their frequency is unknown:
Sepsis leading to death, abnormally low number of blood cells, pulmonary hemorrhage*, damage to the jawbone (secondary to excessive growth of white blood cells), brain disease, tumor lysis syndrome, pathological changes in brain white matter (leukoencephalopathy), increased cerebrospinal fluid pressure, dementia, arachnoiditis, alveolitis, physical weakness, chest pain, hypoxia, ataxia, increased risk of toxic reactions during radiotherapy, skin redness and peeling, swelling, hypersensitivity.
The scaly, red skin patches associated with psoriasis may worsen with exposure to ultraviolet light sources, such as sunlight, and with methotrexate use. Skin problems after radiotherapy (radiation-induced dermatitis) or sunburn may reappear during methotrexate treatment.
* (adverse effect reported for methotrexate used in patients with underlying rheumatological disease).
Reporting of adverse effects
If you experience any adverse effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report adverse effects directly via the national reporting system at the website www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. How to store Metotrexato Aurobindo

Keep this medicine out of the sight and reach of children, preferably in a locked cabinet. Accidental ingestion may be fatal in children.
Do not use this medicine after the expiry date stated on the carton and blister after "EXP.". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Appropriate procedures for the safe handling of cytotoxic agents must be followed.
Anyone handling methotrexate must wash their hands after administering a dose. Disposable gloves are recommended when handling methotrexate tablets.
Women who are pregnant, planning to become pregnant, or breastfeeding must not handle methotrexate.
Unused medicine and waste material arising from this medicine must be disposed of in accordance with local regulations for cytotoxic agents.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Metotrexate Aurobindo contains
The active substance is methotrexate.
Each tablet contains 2.5 mg of methotrexate.
The other components are: microcrystalline cellulose (grade 101), corn starch, pregelatinized starch, microcrystalline cellulose (grade 102), anhydrous colloidal silicon dioxide, magnesium stearate, polysorbate 80.

Description of the appearance of Metotrexate Aurobindo and package contents
Tablets.
Metotrexate Aurobindo 2.5 mg tablets:
Yellow, round, biconvex tablet, marked with '2.5' on one side and smooth on the other side.

Pack sizes:
Blister packs: 10, 12, 20, 24, 25, 30 and 100 tablets.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Eugia Pharma (Malta) Ltd
Vault 14, Level 2, Valletta Waterfront,
Floriana FRN 1914
Malta

Manufacturer
APL Swift Services (Malta) Ltd
HF26, Hal Far Industrial Estate,
Hal Far, Birzebbugia, BBG 3000
Malta

Generis Farmacêutica SA
Rua João de Deus, 19,
2700-487 Amadora
Portugal

Arrow Génériques
26 Avenue Tony Garnier
Lyon, 69007
France

This medicinal product is authorized in the European Economic Area countries under the following names:
France: Methothrexate Arrow 2,5 mg, comprimé
Methotrexate Arrow 10 mg, comprimé sécable
Italy: Metotrexato Aurobindo
Netherlands: Methotrexaat Eugia 2,5 mg tabletten
Methotrexaat Eugia 10 mg tabletten

Methotrexate Aurobindo