Package Insert: Information for the User

Methotrexate Weekly Cipla 2.5 mg Tablets EFG

Read this package insert carefully before taking this medication, as it contains important information for you.

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medication has been prescribed to you alone, and you should not give it to others who may have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this package insert. See section 4.

6. Contents of the pack and additional information

Cipla Methotrexate tablets contain the active ingredient methotrexate. Methotrexate is an antimetabolite and immunosuppressant (a medicine that affects the reproduction of body cells and reduces the activity of the immune system).

Methotrexate is indicated for the treatment of:

• active rheumatoid arthritis in adult patients
• severe, resistant psoriasis that has not responded adequately to other treatments, such as phototherapy, UVA, and retinoids.
• severe psoriatic arthritis in adult patients.

Your doctor will advise you how Cipla Methotrexate tablets may help you in your individual situation.

Do not take Metotrexato Semanal Cipla tablets

• If you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6).
• If you are pregnant or breastfeeding (see section “Pregnancy, lactation and fertility”).
• If you have severe liver dysfunction (your doctor will decide the severity of your disease).
• If you have severe kidney dysfunction (your doctor will decide the severity of your disease).
• If you have or have had bone marrow-related diseases or severe blood disorders.
• If your alcohol consumption is high.
• If you have any immune system diseases.
• If you have severe, acute or existing infections, such as tuberculosis or HIV.
• If you have mouth ulcers or inflammation.
• If you have active gastrointestinal ulcers (for example, peptic ulcer or ulcerative colitis)

Do not undergo vaccination with live vaccines while taking methotrexate.

Warnings and precautions

Consult your doctor, pharmacist or nurse before starting to take Metotrexato Semanal Cipla tablets if you have or have had any of the following conditions:

• If you have or have had any liver or kidney disease.
• If you are taking any other medicine or vitamin supplement (see section “Taking Metotrexato Semanal Cipla tablets with other medicines”).
• If you have stomach ulcers or intestinal ulcers (peptic ulcer or ulcerative colitis).
• If you have a poor general condition.
• If you have recently been vaccinated or plan to be vaccinated.
• If you haveany prolonged and inactive infection (for example, tuberculosis, hepatitis B or C, herpes zoster virus infection).
• If you have diabetes mellitus and are being treated with insulin.
• If you have respiratory function problems.
• If you have severe obesity.
• If you have excess fluid in the abdomen or in the cavity between the lungs and the chest wall (ascitis, pleural effusions)
• If you are dehydrated or have a disease that makes you dehydrated (for example, dehydration caused by vomiting, diarrhea or inflammation of the mouth or lips).

Pulmonary hemorrhage has been reported in patients with underlying rheumatological disease taking methotrexate. If you observe blood when coughing or spitting, you should contact your doctor immediately.

If you have skin problems after radiation therapy (radiation causes dermatitis) or sunburn, as these conditions may recur when taking methotrexate.

Methotrexate can make the skin more sensitive to sunlight. Avoid intense sunlight and do not use sunbeds or ultraviolet lamps without medical advice. To protect your skin from intense sunlight, wear suitable clothing or use a high-factor sunscreen.

Diarhea can be a possible side effect of methotrexate and requires discontinuation of treatment. If you experience diarrhea, please talk to your doctor.

Special precautions for treatment with Metotrexato Semanal Cipla

Methotrexate temporarily affects the production of sperm and eggs, which is reversible in most cases. Methotrexate can cause miscarriage and severe birth defects. If you are a woman, you should avoid becoming pregnant while using methotrexate and for at least six months after completing treatment.If you are a man, you should avoid fathering a child if you are taking methotrexate at the moment and for at least 3 months after stopping treatment.See also section “Pregnancy, lactation and fertility”.

Changes in the skin caused by psoriasis may worsen during treatment with methotrexate if exposed to ultraviolet radiation.

Cerebral disease (encephalopathy/leucoencephalopathy) has been reported as a side effect in patients receiving methotrexate for cancer treatment; it cannot be ruled out that this may also occur when taking methotrexate tablets for the treatment of rheumatoid arthritis or psoriasis.

If you, your partner or caregiver notice the appearance or worsening of neurological symptoms, such as general muscle weakness, vision changes, changes in thinking, memory and orientation that cause confusion and changes in personality, contact your doctor immediately, as these may be symptoms of a rare and serious brain infection called leucoencephalopathy multifocal progressive (LMP).

Precautions and recommended additional tests

Even if methotrexate is used at low doses, serious side effects may occur. To detect them in time, your doctor should perform control tests and analytical tests.

Before starting treatment:

Before starting treatment, your blood will be analyzed to see if you have enough blood cells. Your blood will also be analyzed to check liver function and to see if you have hepatitis. In addition, your blood will be checked for serum albumin (a protein in the blood), hepatitis status (liver infection) and kidney function. Your doctor may also decide to perform other liver tests, some of which may be images of your liver and others may require a small sample of liver tissue for closer examination. Your doctor may also check if you have tuberculosis and take a chest X-ray or perform a respiratory function test.

During treatment:

Your doctor may perform the following checks:

- Examine the oral cavity and pharynx to detect changes in the mucosa, such as inflammation or ulceration;

- Blood test/hemogram with blood cell count and measurement of serum methotrexate levels;

- Blood test to check liver function;

- Diagnostic imaging tests to check liver status;

- Small sample of liver tissue extracted for closer examination;

- Blood test to check kidney function;

- Control of respiratory pathways and, if necessary, respiratory function test.

It is very important that you attend these scheduled checks.

If the results of any of these tests are noteworthy, your doctor will adjust your treatment accordingly.

Older patients

Older patients taking methotrexate should be closely monitored by a doctor to detect any possible side effects as soon as possible.

The age-related deterioration of liver and kidney function, as well as the low vitamin B12 reserves in the elderly, require a relatively low dose of methotrexate.

Children and adolescents

Methotrexate tablets are not indicated for children or adolescents for the treatment of rheumatoid arthritis and psoriasis.

Use of Metotrexato Semanal Cipla tablets with other medicines

Inform your doctor or pharmacist if you are taking, have taken recently or may need to take any other medicine.

The simultaneous use of another medicine may affect the efficacy and safety of this medicine.

Remember to tell your doctor that you are taking methotrexate tablets if they prescribe another medicine while you are still taking the treatment. It is especially important to tell your doctor if you are using:

• metamizol (synonyms novaminsulfon and dipirona) (pain reliever and/or fever medicine);

• some antibiotics (chloramphenicol, penicillins, glycopeptides, sulfonamides, ciprofloxacin, cephalothin, trimethoprim/sulfamethoxazole and tetracyclines);
• diuretics (triamterene);
• blood sugar-lowering medicines such as metformin;
• medicines for epilepsy such as phenytoin or levetiracetam;
• medicine that sequesters bile acids and can be used to lower cholesterol levels (cholestyramine).
• probenecid (medicine for gout treatment);
• vitamin B12 (vitamin supplement);
• omeprazole or pantoprazole (medicines for stomach acid);
• medicines that cause liver and kidney toxicity [such as sulfasalazine and leflunomide (medicines for rheumatic diseases) and alcohol];
• antineoplastic agents (for example, doxorubicin, cisplatin, mercaptopurine);
• medicines used for pain and/or inflammation known as non-steroidal anti-inflammatory drugs (NSAIDs) (for example, diclofenac and ibuprofen, salicylates such as aspirin and pyrazoles such as metamizol);
• other medicines for rheumatoid arthritis or psoriasis such as azathioprine, leflunomide, sulfasalazine (medicine that is also used to treat ulcerative colitis), phenylbutazone, or amidopyrine;
• theophylline (medicine for respiratory diseases);
• ciclosporin (an immunosuppressive agent).
• barbiturates (injection for sleep)
• tranquilizers
• oral contraceptives
• retinoids (used to treat psoriasis and other skin disorders)
• primaquine (used to prevent or treat malaria)
• any type of vaccination with live vaccines (avoid it), such as measles, mumps, flu virus or yellow fever.

Inform your doctor about the use of Metotrexato Semanal Cipla tablets at your next visits.

Use of Metotrexato Semanal Cipla tablets with food, drinks and alcohol

Avoid consuming alcohol as well as excessive consumption of coffee, caffeinated soft drinks and black tea, as they may increase the risk of side effects or interfere with the efficacy of methotrexate during treatment. In addition, make sure you drink enough fluids during methotrexate treatment, as it may increase the risk of dehydration (decrease in body water) and therefore increase the toxicity of methotrexate.

Pregnancy, lactation and fertility

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

Do not use Metotrexato Semanal Cipla during pregnancy or if you are planning to become pregnant. Methotrexate can cause birth defects, harm the fetus or cause miscarriage. It is associated with skull, face, heart and blood vessel malformations, brain and limb malformations. Therefore, it is very important that methotrexate is not administered to pregnant women or those planning to become pregnant. In fertile women, any possibility of pregnancy should be excluded with appropriate measures, for example, a pregnancy test before starting treatment. You should avoid becoming pregnant while taking methotrexate and for at least 6 months after stopping treatment, using reliable contraceptive methods during this time (see also section “Warnings and precautions”).

If you become pregnant during treatment or suspect you may be pregnant, consult your doctor as soon as possible. You will be offered information about the risk of harm to the child during treatment.

If you want to become pregnant, consult your doctor, who may refer you to a specialist to inform you before starting treatment.

Lactation

Do not breastfeed during methotrexate treatment, as methotrexate has been detected in breast milk. If your doctor considers it absolutely necessary to take the medicine, stop breastfeeding your baby.

Fertility

Male fertility

The available data do not indicate a higher risk of malformations or miscarriage if the father takes a methotrexate dose of less than 30 mg/week. However, this risk cannot be completely ruled out. Methotrexate can be genotoxic, meaning it can cause genetic mutations. Methotrexate can affect sperm production and cause birth defects.Therefore, you should avoid fathering a child or donating semen while taking methotrexate and for at least 3 months after stopping treatment.

Consult your doctor or pharmacist before starting treatment.

Driving and operating machines

During methotrexate treatment, you may experience fatigue and dizziness. Do not drive or operate machinery if you have these symptoms.

Metotrexato Semanal Cipla tablets contain lactose and sodium

If your doctor has told you that you have an intolerance to certain sugars, consult thembefore taking this medicine.

This medicine contains less than 1 mmol of sodium (23 mg) per tablet; it is essentially “sodium-free”.

Follow exactly the administration instructions of this medication as indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

• Take metotrexate tablets once a week.
• Patients with rheumatoid arthritis, psoriatic arthritis, or psoriasis should take their tablets orallyonce a weekon the same day each week.
• Do not take the tablets more frequently than indicated by your doctor.
• Daily administration may cause severe toxic effects, including death.
• Take the tablets with a glass of water while sitting or standing.

The recommended dose is

Rheumatoid Arthritis

The recommended dose is 7.5 to 15 mgper oral, once a week.

Psoriasis

The recommended dose is 7.5 to 15 mgper oral, once a week.

Take metotrexate only once a week

Information on taking tablets for rheumatic or skin diseases in adults.

Each package of metotrexate 2.5 mg tablets contains 24 tablets. Each tablet contains a dose of 2.5 mg of metotrexate. The following diagrams show the recommended number of tablets to take for each of the inflammatory indications described above. These diagrams are an example, your doctor may change the dose if required. It is very important that you take the correct number of tablets prescribed by your doctor. Remember also that taking the tablets indicated by your doctor should be done 1 time per week.This medication SHOULD NOT BE TAKEN EVERY DAY for the treatment of rheumatoid arthritis and psoriasis.

Rheumatoid Arthritis and Psoriasis

The initial dose in adults is 3 tablets (7.5 mg) once a week. Therefore, the package of metotrexate that contains 24 tablets covers the treatment for 8 weeks, distributing the tablets as follows:

Initial dosage: 3 tablets of 2.5 mg per week (7.5 mg per week)

Increased dosage: 4 tablets of 2.5 mg per week (10 mg per week)

The dose should be adjusted according to your response to treatment and adverse effects.

Proper procedures should be used for the safe use of cytotoxic agents. Any person who has to be in contact with metotrexate should wash their hands once the dose has been administered. Gloves should be used when coming into contact with metotrexate tablets. Women who are pregnant or planning to become pregnant or breastfeeding should not be in contact with metotrexate.

Use in children

Administration is not recommended in children.

If you take more Metotrexate Cipla tablets than you should

If you take (or someone has taken) more medication than you should, consult a doctor immediately or go immediately to the nearest hospital. In case of overdose or accidental ingestion, consult the Toxicology Information Service, phone 91 562 04 20.

A metotrexate overdose can cause severe toxic reactions, including death. Symptoms of overdose may include: bruises or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomiting with a coffee ground appearance, anddecreased urine production. See section 4.

Carry the medication with you if you go to the doctor or hospital.

If you forgot to take Metotrexate Cipla tablets

If you forget to take your dose, take it as soon as you remember, as long as it is within the next two days. However, if you forget to take your dose for more than two days, contact your doctor for advice.Do not take a double dose to compensate for the missed doses.

Make sure you have enough medication before traveling or vacations.

If you interrupt treatment with Metotrexate Cipla tablets

Do not interrupt treatment with metotrexate unless your doctor tells you to. If you have to stop treatment, your doctor will decide the best method for you.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Generally, the incidence and severity of metotrexate side effects are related to the dose and frequency of administration. Most side effects are reversible if detected early.

Severe side effects

Seek medical attention or go to the hospital immediately if you experience any of the following symptoms.

Rare (may affect 1 in 100 people)

• Chest tightness, difficulty breathing, fever, or shortness of breath. You may be at risk of pulmonary fibrosis or pneumonia.

• Chest pain, difficulty breathing, facial, neck, or hand swelling, dizziness, or fainting. These may be signs of a severe allergic reaction.
• Severe skin reactions such as peeling and blistering in the mouth, eyes, and genitals, as well as numerous pus-filled eruptions, fever. You may be experiencing Stevens-Johnson syndrome or toxic epidermal necrolysis.
• Sunburn-like reactions due to increased skin sensitivity to sunlight..
• Fever and general deterioration, or fever with localized infections such as in the throat or mouth. You may have a reduced white blood cell count (possibly due to bone marrow depression) and may be more susceptible to infections.
• Urination pain or difficulty.
• Renal deterioration.

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

• Loss of appetite, nausea, skin itching, yellowing of the skin or eyes, fever, swelling, or distension of the stomach. You may be experiencing liver damage or inflammation.
• Vomiting blood, black stools like tar, and stomach pain. You may be experiencing bleeding or stomach ulcers.
• Cramping pain, acute pain, or swelling in the leg, redness, difficulty breathing, chest pain, or sudden collapse. You may have a blood clot.
• Reduced or lost urine production.
• Fever, chills, rapid heartbeat, rapid breathing, confusion, or dizziness. You may be experiencing sepsis due to an infection.

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

• Blood in the urine.
• Difficulty speaking or communicating.
• Seizures.

Unknown (frequency cannot be estimated from available data)

• Blood when coughing or sneezing.
• Certain brain disorders (encephalopathy/leucoencephalopathy).

Other side effects

Very common (may affect more than 1 in 10 people)

• Throat inflammation or pain in the mouth or lips,
• Indigestion,
• Loss of appetite,
• Nausea,
• Vomiting,
• Stomach pain,
• Increased liver enzymes

Common(may affect 1 in 10 people)

• Infections
• Dyspepsia
• Diarrhea
• Fatigue
• Coughing
• Mareos
• Enrojecimiento or large red patches on the skin
• Hair loss
• Somnolence
• Exanthema
• Ulcers in the mouth

Rare(may affect 1 in 100 people)

• Bleeding tendency
• Change in blood count
• Anemia
• Itching skin
• Lymph node inflammation that may be a sign of lymphoma
• Vaginal inflammation and ulcers
• Dizziness
• Fatty liver
• Decreased serum albumin levels
• Herpes-like eruptions on the skin
• Increased skin pigmentation,
• Osteoporosis,
• Muscle and joint pain
• Local tissue swelling
• Urinary ulcers
• Chills

Rare(may affect 1 in 1,000 people)

• Depression
• Confusion
• Weakness on one side of the body (hemiparesis)
• Diabetes
• Low blood pressure (hypotension)
• Shortness of breath
• Pharyngeal inflammation
• Throat pain
• Acne
• Clearing of the skin
• Itchy skin rash
• Burning sensations in psoriatic skin lesions
• Ulcers on the skin
• Herpes or painful eruptions
• Menstrual changes
• Impotence
• Reduced libido
• Condition characterized by the appearance of very large red blood cells (megaloblastic anemia)
• Mood fluctuations
• Inflammation of the heart sac, accumulation of fluid in the heart sac
• Inflammation of the small intestine
• Blood in stool
• Nail shedding
• Dark spots on the nails
• Red or purple patches due to blood vessel bleeding
• Allergic inflammation of blood vessels
• Lesions similar to sunburn or radiation dermatitis
• Stress fractures
• Abnormal levels of electrolytes in the blood
• Physical weakness
• Fever
• Slow wound healing
• Respiratory arrest

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

• Immune deficiency (hypogammaglobulinemia)
• Irritation
• Somnolence, fatigue (letargo)
• Vision changes
• Conjunctivitis (redness and irritation of the thin membrane covering the eye)
• Liquids or swelling in the heart sac or lungs.
• Inflammation of blood vessels, often with skin rash (vasculitis)
• Pulmonary infection
• Dry cough
• Vomiting blood
• Furuncles
• Hematomas or capillaries on the skin surface
• Fertility problems
• Reduced sperm count
• Infertility
• Vaginal bleeding or discharge
• Male breast enlargement
• Lymphoproliferative disorders (excessive increase in white blood cells)
• Severe bone marrow disorders
• Increased susceptibility to infections
• Insomnia
• Psychosis
• Low antibody levels
• Mild cognitive impairment (“foggy mind”)
• Strange sensations in the head
• Cerebral inflammation
• Tinnitus
• Pain
• Muscle weakness
• Tickling
• Changes in taste (metallic taste)
• Inflammation of the brain membranes
• Paralysis
• Inflammation of the lung membranes
• Liver insufficiency
• Inflammation of blood vessels
• Chronic obstructive pulmonary disease
• Inflammation of sweat glands
• Infections of the nails
• Sensation of numbness or tingling/sensitivity to stimuli less than normal

Unknown(frequency cannot be estimated from available data)

• Abnormally low blood cell count
• Sepsis with fatal outcome
• Fetal death
• Fetal damage
• Increased risk of toxicity during radiation therapy
• Increased number of white blood cells and inflammation of lung tissue
• May worsen red and scaly plaques associated with psoriasis when exposed to ultraviolet light, such as sunlight, in combination with metotrexate.
• Pulmonary hemorrhage
• Damage to the jaw bones (secondary to excessive white blood cell increase)
• Reactivation of chronic inactive infections
• Vision problems
• Retinal damage
• Colon enlargement due to inflammation/infection
• Pancreatitis
• Pathological changes in the white matter of the brain (leucoencephalopathy)
• Nasal hemorrhage
• Asthma
• Presence of proteins in the urine
• Redness and peeling of the skin
• Swelling

Reporting of side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the Spanish System for the Pharmacovigilance of Medicines for Human Use: https://www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

This medication does not require any special storage temperature.

Blister: Store the blister in the outer packaging to protect it from light.

HDPE Bottle:Store in the original packaging to protect it from light.

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

Medications should not be disposed of through drains or trash. Dispose of the packaging and medications you no longer need at the SIGRE point of the pharmacy.Ask your pharmacist if you are unsure how to dispose of the packaging and medications you no longer need. This will help protect the environment.

Composition of Metotrexato Cipla tablets

• The active ingredient is metotrexato.
• • Metotrexato Cipla 2.5 mg tablets: each tablet contains 2.5 mg of metotrexato.
• The other components are:anhydrous calcium hydrogen phosphate,monohydrate lactose,potassium starch glycolate,microcrystalline cellulose, talc, and magnesium stearate.

Appearance of the product and contents of the package

Metotrexato Cipla 2.5 mg tablets are yellow, circular, biconvex, and smooth on both sideswith dimensions of 4.50 mm ± 0.2 mm.

Metotrexato 2.5 mg tablets are presented in HDPE bottles containing 25 or 100 tablets and in blister packaging of 10, 24, 25, 28, 30, 50, or 100 tablets.

Only some package sizes may be marketed.

Marketing Authorization Holder

Cipla Europe NV

De Keyserlei 58-60,

Box 19, 2018Antwerp

Belgium.

Responsible for manufacturing

Cipla Europe NV

De Keyserlei 58-60,

Box 19, 2018Antwerp

Belgium.

S&D Pharma CZ

spol. s.r.o, Theodor 28

Pchery (Pharmos a.s. facility), 27308

Czech Republic.

Local Representative

Cipla Europe NV subsidiary in Spain

C/ Guzmán el Bueno, 133 Edif Britannia

28003 Madrid

Spain

This medicine is authorized in the member states of the European Economic Area with the following names:

Last review date of this leaflet: October 2024

The detailed information on this medicine is available on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

Patient card

THIS PATIENT CARD IS INTENDED ONLY FOR PATIENTS USING METOTREXATO-CONTAINING MEDICINES FOR ARTHRITIS AND PSORIASIS.

IF YOU USE METOTREXATO FOR ANY OF THE ABOVE-MENTIONED DISEASES, YOU MUST TAKE METOTREXATO ONLY ONCE A WEEK.

Write down the day of the week when you administer: ______________

Do not take a dose greater than the one prescribed.

Overdose may cause severe side effects and can be fatal. Symptoms of overdose include: sore throat, fever, mouth ulcers, diarrhea, vomiting, skin rash, bleeding, or unusual weakness. If you believe you have taken an excessive dose, seek medical attention immediately.

Always show this card to healthcare professionals who are not familiar with your treatment with metotrexato to warn them about your weekly use (e.g., in hospital admission, caregiver change).

For more information, read the leaflet included in the package.

Information on risk prevention authorized by the Spanish Agency of Medicines and Medical Devices (AEMPS). April 2020.

Available on the AEMPS website www.aemps.gob.es