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Package leaflet: Information for the user Methotrexate Orion 2.5 and 10 mg tablets

Methotrexate

Read all of this leaflet carefully before

you start taking this medicine because it

contains important information for you.

-    Keep this leaflet. 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 them, even if their signs of illness are the same as yours.

-    If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Methotrexate Orion is and what it is used for

2.    What you need to know before you take Methotrexate Orion

3.    How to take Methotrexate Orion

4.    Possible side effects

5.    How to store Methotrexate Orion

6.    Contents of the pack and other information

1. What Methotrexate Orion is and what it is used for

The active substance of Methotrexate Orion tablets, methotrexate, is a substance with the following properties:

-    it interferes with the growth of certain cells in the body that reproduce quickly and hence slows down the growth of tumour cells

-    it reduces the activity of the immune system (the body's own defence mechanism)

-    it has anti-inflammatory effects. Methotrexate is used to treat:

-    active rheumatoid arthritis in adult patients

-    severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA and retinoids

-    severe psoriatic arthritis in adult patients

-    maintenance therapy in acute lymphoblastic leukaemia.

Your doctor will be able to explain how Methotrexate Orion tablets might help you in your particular condition.

2. What you need to know before you take Methotrexate Orion

Do not take Methotrexate Orion:

-    if you are allergic (hypersensitive) to methotrexate, or any of the other ingredients of this medicine (listed in section 6)

-    if you are pregnant or breast-feeding (see section "Pregnancy, breast-feeding and fertility")

-    if you have significant liver disease (your doctor decides the severity of your disease)

-    if you have significant kidney disease (your doctor decides the severity of your disease)

-    if you have or have had a bone marrow disease or serious blood disorders

-    if you have severe acute or chronic infections or immunodeficiency syndrome

-    if you suffer from alcoholism.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Methotrexate Orion if you suffer from or have suffered in the past from any of the following conditions:

-    have or have had any liver or kidney disease

-    are using any medicines or vitamin products (see section "Other medicines and Methotrexate Tablets")

-    have ulcerations in your stomach or bowel (peptic ulcer or ulcerative colitis)

-    are in poor general condition

-    have received any vaccinations recently or are you due to have any

-    have any symptoms or signs of infection

-    diabetes mellitus treated with insulin. Methotrexate temporarily affects sperm and egg production. You and your partner should avoid conception (becoming pregnant or fathering children) if currently receiving Methotrexate Orion and for at least six months after your treatment with methotrexate has stopped. See section "Pregnancy, breast-feeding and fertility". Before treatment is started your doctor may carry out blood tests, and also to check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests.

If you take Methotrexate Orion for psoriasis or reumatoid arthritis, make sure you take a single dose once per week or divide this dose and take it in 3 doses weekly at 12 hours' interval. If you mistakenly take Methotrexate Orion more than once a week serious adverse effects may occur. In case of doubts regarding the dosage please consult your doctor, pharmacist or nurse. Children, adolescents and elderly Children, adolescents and the elderly should be kept under particularly close medical surveillance during treatment with Methotrexate Orion, in order to identify possible side effects as early as possible. Use in children below 3 years of age is not recommended due to the insufficient experience in this age group.

Other medicines and Methotrexate Orion

Other concomitant medication may affect the efficacy and safety of this medicine. Methotrexate Orion may also affect the efficacy and safety of other medications.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Remember to tell your doctor about your treatment with Methotrexate Orion, if you are prescribed

another medicine while the treatment is still ongoing. It is especially important to tell your doctor if you are using:

-    certain antibiotics (such as penicillins, sulfonamides, ciprofloxacin, cefalotin, trimethoprim/sulfamethoxazole, tetracycline and chloramphenicol)

-    agents that may be harmful to kidneys, liver or blood [e.g. sulfasalazine, azathi-oprine and leflunomide (medicines for rheumatic diseases), vitamin A and its derivatives, alcohol]

-    other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, ciclosporin)

-    anticancer agents (e.g. mercaptopurine and 5-fluorouracil)

-    anticonvulsant medicines (e.g. phenyt-oin and carbamazepine)

-    aspirin or similar medicines (known as salicylates)

-    non-steroidal anti-inflammatory medicines (medicines taken for pain relief) e.g. ibuprofen and pyrazoles

-    omeprazole or pantoprazole (medicine used to stop the production of stomach acid)

-    diuretics (water tablets)

-    probenecid (medicine used to treat gout)

-    folic acid (vitamin preparation)

-    theophylline (medicine used to treat respiratory diseases)

-    vitamin preparations or other products containing folic acid.

Methotrexate Orion with food, drink and alcohol

Alcohol as well as large amounts of coffee, caffeine-containing soft drinks and black tea should be avoided during treatment with Methotrexate Orion.

Pregnancy, breast-feeding and fertility If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Pregnancy

Do not use Methotrexate Orion during pregnancy or if you are trying to become pregnant.

Methotrexate can cause birth defects, harm unborn babies or cause miscarriages and so it is very important that it is not given to pregnant patients or patients planning to become pregnant. Therefore, in women of child-bearing age any possibility of pregnancy must be excluded with appropriate measures, e.g. a pregnancy test, before starting treatment. You must avoid becoming pregnant whilst taking methotrexate and for at least 6 months after treatment is stopped. Therefore you must ensure reliable contraception during this whole period (see section "Warnings and precautions").

If you do become pregnant during treatment, you should be offered advice regarding the risk of harmful effects on the child through treatment.

If you wish to become pregnant you should consult a genetic information centre before the planned start of treatment, because methotrexate may be genotoxic, which means that the medicine may cause genetic mutation.

Breast-feeding

Do not breastfeed during treatment, because methotrexate passes into breast milk. If your attending doctor considers treatment with methotrexate absolutely necessary during the lactation period, you must stop breast-feeding.

Fertility Male fertility

Methotrexate Orion may be genotoxic. This means that the medicine may cause genetic mutation. Methotrexate can affect sperm and egg production with the potential to cause birth defects. Therefore, you must avoid fathering a child whilst taking methotrexate and for at least 6 months after treatment is stopped. Since treatment with methotrexate may lead to infertility, it might be advisable for male patients to look into the possibility of sperm preservation before starting treatment (see section "Warnings and precautions").

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines You can feel fatigue and dizziness during Methotrexate Orion treatment. Do not drive or use machines if you have such symptoms. Methotrexate Orion contains lactose These tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

3. How to take Methotrexate Orion

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

-    Take Methotrexate Orion once a week

-    Patients with rheumatoid arthritis or psoriasis will usually take their tablets orally once a week on the same day each week.

-    Do not take tablets more often than your doctor has told you to.

-    Daily administration can lead to serious toxic effects, including death

-    Take the tablets with a glass of water whilst sitting upright or standing.

Dosage for rheumatoid arthritis, psoriasis and severe psoriatic arthritis You will usually take your tablets once a week on the same day each week. The dose will normally be between 7.5 and 15 mg.The weekly dose may be administered in three divided doses during 24 hours (at 12 hours' interval).

Dosage for treatment of tumours The doctor will calculate the dosage required from your body surface. Your doctor will decide the correct dose for you. If you want more information you should ask your doctor.

Special populations

Usually reduced dose according to doctor's prescription is used for elderly patients and for patients with renal or hepatic

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impairment. See also section 2. "Do not take Methotrexate Orion".

Use in children and adolescents

For children and adolescents with maintenance therapy in acute lymphoblastic leukaemia the doctor will calculate the dose individually, depending on the body surface.

Safe handling of Methotrexate Orion tablets

Proper procedures for safe handling of cytotoxic agents should be administered. Disposable gloves should be used when handling methotrexate tablets. Pregnant women should avoid handling methotrexate tablets, if possible.

If you take more Methotrexate Orion than you should

If you take (or someone else has taken) more of the medicine than you should, a physician or nearest hospital casualty department must be contacted immediately.

An overdose of methotrexate can lead to severe toxic reactions, including death. Overdose symptoms may include easy bruising or bleeding, unusual weakness, mouth sores, nausea, vomiting, black or bloody stools, coughing up blood or vomit that looks like coffee grounds, and decreased urinating. See also section 4 "Possible side effects".

Take your medicine package with you if you go to a doctor or hospital. If you used too much methotrexate you will receive calcium folinate to lessen the side effects of methotrexate.

If you forget to take Methotrexate Orion

Take the forgotten dose as soon as you remember if this is within two days. However, if you have missed a dose by more than two days, please contact your doctor for advice. Do not take a double dose to make up for a forgotten dose.

Make sure before your holiday or trip that you have enough of your medicine.

If you stop taking Methotrexate Orion Do not stop taking Methotrexate Orion unless your doctor tells you to. Should you need to stop taking Methotrexate Orion, your doctor will have decided which is the best method for you.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

ma multiforme, burning in skin psoriatic lesions, skin ulcers)

-    herpes zoster

-    decreased bone mineral density a type of bone disease (osteoporosis)

-    increase in rheumatic nodules

-    pain in joint or muscles

-    menstrual disorders

-    impotence

-    decrease of libido

-    fatal whole-body inflammation (sepsis). Very rare (may affect up to 1 in 10,000 people)

-    immune deficiency (hypogammaglob-ulinaemia)

-    irritation

-    difficulty in speaking (dysarthria)

-    sleepiness, tiredness (lethargy)

-    visual disturbance

-    redness and irritation of the thin membrane that covers the eye (conjunctivitis)

-    fluid in the sac around the heart. May cause cardiac tamponade which is a life threatening condition where the heart is unable to pump correctly due to the external pressure. May require medical intervention to drain the fluid and remove the pressure

-    inflammation of blood vessels, often with skin rash (vasculitis)

-    infection of lungs

-    dry cough

-    loss of sex drive

-    low sperm count

-    vaginal bleeding.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system, see below. By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie

Like all medicines, this medicine can cause side effects, although not everybody gets them. In general, the incidence and severity of adverse reactions of methotrexate are related to dose and frequency of administration. Most adverse reactions are reversible if detected early.

If you notice any of the following, please contact your doctor immediately:

-    unusual bleeding (including vomiting blood) or bruising

-    severe diarrhoea

-    ulcers in mouth

-    an allergic reaction such as skin rash or swelling of your lips or tongue

-    fever

-    yellowing of the skin (jaundice)

-    pain or difficulty in passing urine

-    thirst and/or frequent urination

-    chest pain

-    a dry cough and/or pain or difficulty in breathing or shortness of breath

-    blurred or decreased vision.

Most of the effects listed below will only be seen in patients who are receiving high doses of methotrexate to treat cancer. They are not seen as often and are not as severe at the doses used in the treatment of psoriasis or rheumatoid arthritis.

Common (may affect up to 1 in 10 people)

-    leukopenia (decrease number of white blood cells)*

-    nausea

-    vomiting

-    diarrhoea

-    unusual fatigue

-    headache

-    dizziness

-    loss of appetite

-    erythematous rashes

-    stomatitis (soreness of the mouth and lips)

-    increase of liver transaminases (enzymes)*

-    decreased resistance to infections

-    tingling or numbness in the hands or feet

-    alopecia.

Uncommon (may affect up to 1 in 100 people)

-    bone marrow depression manifested by thrombocytopenia and other abnormalities developing in the blood*

-    formation of excess fibrous connective tissue in an organ (fibrosis)

-    inflammation of the lungs, which can cause shortness of breath and difficulty breathing

-    itchy skin

-    anemia

-    nosebleed

-    skin condition that causes painful blisters and sores of the skin and mucous membranes, especially in the mouth (Stevens-Johnson syndrome)

-    serious illness with blistering of the skin (toxic epidermal necrolysis)

-    anaphylactic reactions

-    kidney dysfunction

-    a cancer of the lymph nodes (or tissues)

-    vaginal ulceration.

* Only detected by your doctor.

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

-    depression

-    confusion

-    hemiparesis (impairment of motor function affecting only one side of the body)

-    diabetes mellitus

-    hypotension

-    thromboembolism

-    dyspnoea

-    gastrointestinal ulceration and bleeding

-    liver damage (hepatic toxicity, periportal fibrosis, hepatic cirrhosis, acute hepatitis)

-    skin reactions (acne, skin depigmentation, urticaria, photosensitivity, erythe

5. How to store Methotrexate Orion

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

Do not use this medicine after the expiry date which is stated on the bottle, blister or the outer carton. The expiry date refers to the last day of that month.

This medicinal product does not require any special temperature storage conditions. Keep the tablet container or blisters in the outer carton, in order to protect from light. Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Methotrexate Orion contains

-    The active substance is methotrexate. Each tablet contains 2.5 mg or 10 mg methotrexate (as methotrexate disodium).

-    The other ingredients are lactose monohydrate, microcrystalline cellulose and magnesium stearate.

What Methotrexate Orion looks like and contents of the pack Methotrexate Orion 2.5 mg tablets: Yellow, round, uncoated, flat tablet, scored and engraved with ORN 57 on one side, diameter 6 mm. The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses. Methotrexate Orion 10 mg tablets: Yellow, round, uncoated, flat tablet, scored and engraved with ORN 59 on one side, diameter

10.5    mm. The tablet can be divided into equal doses.

Pack sizes:

Bottle with child-resistance closure

2.5    mg: 10, 12, 24, 28, 30, 50 and 100 tablets. 10 mg: 10, 15, 25, 50 and 100 tablets.

Blister pack

2.5    mg: 24, 50 and 100 tablets.

Not all pack sizes may be marketed. Marketing Authorisation Holder

Orion Corporation Orionintie 1 FI-02200 Espoo Finland

Manufacturer

Orion Corporation Orion Pharma Orionintie 1 FI-02200 Espoo Finland

This leaflet was last revised:

22.06.2016