Package leaflet: Information for the user

Metopen 7.5 mg solution for injection in pre-filled pen

Metopen 10 mg solution for injection in pre-filled pen

Metopen 12.5 mg solution for injection in pre-filled pen

Metopen 15 mg solution for injection in pre-filled pen

Metopen 17.5 mg solution for injection in pre-filled pen

Metopen 20 mg solution for injection in pre-filled pen

Metopen 22.5 mg solution for injection in pre-filled pen

Metopen 25 mg solution for injection in pre-filled pen

Metopen 27.5 mg solution for injection in pre-filled pen

Metopen 30 mg solution for injection in pre-filled pen

methotrexate

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 further questions, ask your doctor or pharmacist.

• 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 or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Metopen is and what it is used for

Metopen is indicated for the treatment of

• Severe, 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, and severe psoriatic arthritis in adult patients.

Rheumatoid arthritis (RA) is a chronic collagen disease, characterised by inflammation of the synovial membranes (joint membranes). These membranes produce a fluid which acts as a lubricant for many joints. The inflammation causes thickening of the membrane and swelling of the joint.

Juvenile arthritis concerns children and adolescents less than 16 years. Polyarthritic forms are indicated if 5 or more joints are affected within the first 6 months of the disease.

Psoriasis is a common chronic skin disease, characterised by red patches covered by thick, dry, silvery, adherent scales.

Psoriatic arthritis is a kind of arthritis with psoriatric lesions of the skin and nails, especially at the joints of fingers and toes.

Metopen modifies and slows down the progression of the disease.

2. what you need to know before you use Metopen

Do not use Metopen if you

• are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6).

• suffer from liver or severe kidney diseases or blood diseases.

• regularly drink large amounts of alcohol.

• suffer from a severe infection, such as tuberculosis, HIV or other immunodeficiency syndromes.

• suffer from mouth ulcers, stomach ulcer or intestinal ulcer.

• are pregnant or breast‑feeding.

• receive vaccinations with live vaccines at the same time.

Warnings and precautions

Talk to your doctor or pharmacist before taking Metopen if you:

• are elderly or if you feel generally unwell and weak.

• have problems with the way your liver works.

• suffer from dehydration (water loss).

Recommended follow‑up examinations and safety measures:

Even when Metopen is administered in low doses, severe side effects can occur. In order to detect them in time, check‑ups and laboratory tests have to be carried out by your doctor.

Before therapy:

Before starting the treatment, blood samples will be taken in order to check that you have enough blood cells, tests to check your liver function, serum albumin (a protein in the blood) and kidney function. Your doctor will also check if you suffer from tuberculosis (infectious disease in combination with little nodules in the affected tissue) and a chest X‑ray will be taken.

During therapy:

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

• Examination of the mouth and throat for changes of the mucosa.

• Blood tests.

• Check of liver function.

• Check of kidney function.

• Check of respiratory system and if necessary lung function test.

Methotrexate may affect your immune system and vaccination results. It may also affect the result of immunological tests. Inactive, chronic infections (such as herpes zoster [shingles], tuberculosis, hepatitis B or C) may flare up. During therapy with Metopen you must not be vaccinated with live vaccines.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

Enlarged lymph nodes (lymphoma) may occur and if this is the case, therapy must be stopped.

Diarrhoea can be a possible side effect of Metopen and requires an interruption of therapy. If you suffer from diarrhoea please speak to your doctor.

Certain brain disorders (encephalopathy/ leukoencephalopathy) have been reported in cancer patients receiving methotrexate. Such side effects cannot be excluded when methotrexate is used to treat other diseases.

Other medicines and Metopen

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Please note that this also applies to medicines that you will take in the future.

The effect of the treatment may be affected if Metopen is administered at the same time as certain other medicines:

• Antibiotics such as: tetracyclines, chloramphenicol, non-absorbable broad‑spectrum antibiotics, penicillines, glycopeptides, sulphonamides, ciprofloxacin and cefalotin (medicines to prevent/ fight certain infections).

• Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or inflammation such as acetylsalicylic acid, diclofenac and ibuprofen or pyrazole).

• Probenecid (medicine against gout).

• Weak organic acids like loop diuretics (“water tablets”).

• Medicines, which may have adverse effects on the bone marrow, such as trimethoprim-sulphamethoxazole (an antibiotic) and pyrimethamine.

• Other medicines used to treat rheumatoid arthritis such as leflunomide, sulphasalazine and azathioprine.

• Mercaptopurine (a cytostatic agent).

• Retinoids (medicine against psoriasis and other dermatological diseases).

• Theophylline (medicine against bronchial asthma and other lung diseases).

• Some medicines against stomach trouble such as omeprazole and pantoprazole.

• Hypoglycaemics (medicines that are used to lower the blood sugar).

Vitamins containing folic acid may impair the effect of your treatment and should only be taken when advised by your doctor.

Vaccination with live vaccine must be avoided.

Metopen 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 Metopen.

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.

Do not take Metopen during pregnancy. There is a risk of harm to the foetus and miscarriage. Men and women should use an effective method of birth control during treatment and during a further six months after treatment with Metopen has been discontinued.

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, such as pregnancy test, prior to therapy.

As methotrexate can be genotoxic, all women who wish to become pregnant are advised to consult a genetic counselling centre, if possible, already prior to therapy. Men should seek advice about the possibility of sperm preservation before starting therapy.

Stop breast‑feeding prior to and during treatment with Metopen.

Driving and using machines

Treatment with Metopen may cause adverse reactions affecting the central nervous system, such as tiredness and dizziness. Thus the ability to drive a vehicle and/or to operate machines may, in certain cases, be compromised. If you feel tired or drowsy do not drive or use machines.

Metopen contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose; i.e. essentially “sodium-free”.

3. How to use Metopen

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

Your doctor decides on the dosage, which is adjusted individually to you. Usually it takes 4 – 8 weeks before there is any effect of the treatment.

Metopen is administered subcutaneously (under the skin) by or under the supervision of a physician or healthcare staff as an injection once a week only. Together with your doctor you decide on a suitable weekday each week on which you receive your injection.

Use in children and adolescents

The doctor decides on the appropriate dose in children and adolescents with polyarthritic forms of juvenile idiopathic arthritis.

Metopen is not recommended in children less than 3 years of age due to insufficient experience in this age group.

Method and duration of administration

Metopen is injected once weekly!

The duration of the treatment is determined by the treating physician. Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris and psoriatic arthritis with Metopen is a long-term treatment.

At the start of your therapy, Metopen will be injected by medical staff. However, your doctor may decide that you are able to learn how to inject Metopen under the skin yourself. You will then receive appropriate training.

Under no circumstances should you try to inject Metopen yourself before you have received such training.

You can also find guidance on how to use Metopen in the section “Instructions for use” at the end of this leaflet.

Please note that all of the contents have to be used.

The manner of handling and throwing away of the medicine and pre‑filled pen must be in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Metopen.

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with plenty of water.

If you use more Metopen than you should

If you use more Metopen than you should, talk to your doctor immediately.

If you forget to use Metopen

Do not take a double dose to make up for a forgotten dose.

If you stop using Metopen

If you stop using Metopen, talk to your doctor immediately.

If you have the impression that the effect of Metopen is too strong or too weak, talk to your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequency as well as the degree of severity of the side effects depends on the dosage level and the frequency of administration. As severe side effects may occur even at low dosage, it is important that you are monitored regularly by your doctor. Your doctor will do tests to check for abnormalities developing in the blood (such as low white blood cells, low platelets, lymphoma) and changes in the kidneys and the liver.

Tell your doctor immediately if you experience any of the following symptoms, as these may indicate a serious, potentially life-threatening side effect, which requires urgent specific treatment:

• persistent dry, non-productive cough, shortness of breath and fever; these may be signs of an inflammation of the lungs [common]

• symptoms of liver damage such as yellowing of the skin and whites of the eyes; methotrexate can cause chronic liver damage (liver cirrhosis), formation of scar tissue in the liver (liver fibrosis), fatty degeneration of the liver [all uncommon], inflammation of the liver (acute hepatitis) [rare] and liver failure [very rare]

• allergy symptoms such as skin rash including red itchy skin, swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing) and feeling you are going to faint; these may be signs of severe allergic reactions or an anaphylactic shock [rare]

• symptoms of kidney damage such as swelling of the hands, ankles or feet or changes in frequency of urination or decrease (oliguria) or absence of urine (anuria); these may be signs of kidney failure [rare]

• symptoms of infections, e.g. fever, chills, achiness, sore throat; methotrexate can make you more susceptible to infections. Severe infections like a certain type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis) may occur [rare]

• symptoms such as weakness of one side of the body (stroke) or pain, swelling, redness and unusual warmth in one of your legs (deep vein thrombosis); This may happen when a dislodged blood clot causes a blockage of a blood vessel (thromboembolic event) [rare]

• fever and serious deterioration of your general condition, or sudden fever accompanied by a sore throat or mouth, or urinary problems; methotrexate can cause a sharp fall in certain white blood cells (agranulocytosis) and severe bone marrow suppression [very rare]

• unexpected bleeding, e.g. bleeding gums, blood in the urine, vomiting blood or bruising, these can be signs of a severely reduced number of blood platelets caused by severe courses of bone marrow depression [very rare]

• symptoms such as severe headache often in combination with fever, neck stiffness, feeling sick, vomiting, disorientation and sensitivity to light may indicate an inflammation of the membranes of the brain (acute aseptic meningitis) [very rare]

• certain brain disorders (encephalopathy/ leukoencephalopathy) have been reported in cancer patients receiving methotrexate. Such side effects cannot be excluded when methotrexate therapy is used to treat other diseases. Signs of this kind of brain disorders may be altered mental state, movement disorders (ataxia), visual disturbances or disturbances of memory [not known]

• severe skin rash or blistering of the skin (this can also affect your mouth, eyes and genitals); these may be signs of conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal necrolysis /Lyell’s syndrome) [very rare]

In the following, please find the other side effects that may occur:

Very common: may affect more than 1 in 10 people

• Inflammation of the mouth lining, indigestion, feeling sick, loss of appetite, abdominal pain.

• Abnormal liver function test (ASAT, ALAT, bilirubin, alkaline phosphatase).

Common: may affect up to 1 in 10 people

• Mouth ulcers, diarrhoea.

• Rash, reddening of the skin, itching.

• Headache, tiredness, drowsiness.

• Reduced blood cell formation with decrease in white and/or red blood cells and/or platelets.

Uncommon: may affect up to 1 in 100 people

• Throat inflammation.

• Inflammation of the bowels, vomiting, inflammation of pancreas.

• Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, skin ulcer, shingles, inflammation of blood vessels, herpes-like skin rash, hives.

• Onset of diabetes mellitus.

• Dizziness, confusion, depression.

• Decrease in serum albumin.

• Decrease in the number of all blood cells and platelets.

• Inflammation and ulcer of the urinary bladder or vagina, reduced kidney function, disturbed urination.

• Joint pain, muscle pain, reduction of bone mass.

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

• Inflammation of gum tissue.

• Increased skin pigmentation, acne, blue spots on the skin due to vessel bleeding (ecchymosis, petechiae), allergic inflammation of blood vessels.

• Decreased number of anti-bodies in the blood.

• Infection, (incl. reactivation of inactive chronic infection), red eyes (conjunctivitis).

• Mood swings (mood alterations).

• Visual disturbances; which may be due to damage to the optic nerves (optic neuropathy)

• Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart and obstruction of cardiac filling due to fluid in the sac around the heart.

• Low blood pressure.

• Formation of scar tissue in the lung (pulmonary fibrosis), shortness of breath and bronchial asthma, accumulation of fluid in the sac around the lung.

• Stress fractures.

• Electrolyte disturbances.

• Fever, wound-healing impairment.

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

• Acute toxic dilatation of the gut (toxic megacolon).

• Increased pigmentation of the nails, inflammation of the cuticles (acute paronychia), deep infection of hair follicles (furunculosis), visible enlargement of small blood vessels.

• Pain, loss of strength or sensation of numbness or tingling in arms and legs, changes in taste (metallic taste), convulsions, paralysis, meningism

• Impaired vision, non-inflammatory eye disorder (retinopathy).

• Loss of sexual drive, impotence, male breast enlargement, defective sperm formation (oligospermia), menstrual disorder, vaginal discharge.

• Enlargement of lymphatic nodes (lymphoma).

Not known: frequency cannot be estimated from the available data

• Increased number of white blood cells.

• Nosebleed.

• Proteins in urine.

• Feeling of weakness.

Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions (such as burning sensations, erythema, swelling, discolouration, severe itching, pain) were observed, decreasing during therapy.

Reporting of side effects

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

[To be completed nationally]

5. How to store Metopen

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

Store below 25 °C.

Keep the pre-filled pens in the outer carton in order to protect from light.

Do not use this medicine after the expiry date stated on the carton and pre-filled pen after EXP. The expiry date refers to the last day of that month.

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 Metopen contains

• The active substance is methotrexate.

1 pre-filled pen with 0.15 ml solution contains 7.5 mg methotrexate.

1 pre-filled pen with 0.2 ml solution contains 10 mg methotrexate.

1 pre-filled pen with 0.25 ml solution contains 12.5 mg methotrexate.

1 pre-filled pen with 0.3 ml solution contains 15 mg methotrexate.

1 pre-filled pen with 0.35 ml solution contains 17.5 mg methotrexate.

1 pre-filled pen with 0.4 ml solution contains 20 mg methotrexate.

1 pre-filled pen with 0.45 ml solution contains 22.5 mg methotrexate.

1 pre-filled pen with 0.5 ml solution contains 25 mg methotrexate.

1 pre-filled pen with 0.55 ml solution contains 27.5 mg methotrexate.

1 pre-filled pen with 0.6 ml solution contains 30 mg methotrexate.

• The other ingredients are sodium chloride, sodium hydroxide and hydrochloric acid for pH adjustment and water for injections.

What Metopen looks like and contents of the pack

This medicinal product is presented as a solution for injection in pre-filled pen.

The solution is clear, yellow-brown.

The following pack sizes are available:

Metopen is available in packs of 1, 2, 4, 5, 6, 10, 11, 12, 14, 15, and 24 pre-filled pens. Alcohol pads are included in the package.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

This medicinal product is authorised in the Member States of the EEA under the following names:

Sweden: Metopen

France: Metoject PEN

This leaflet was last revised in 23 March 2016

Instructions for use

Recommendations

• Carefully read the instructions below before starting your injection.

• Always use the injection technique advised by your doctor, pharmacist or nurse.

Additional information

The manner of handling and throwing away of the medicine and pre‑filled pen must be in accordance with local requirements. Pregnant healthcare personnel should not handle and/or administer Metopen.

Methotrexate should not come into contact with the surface of the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with plenty of water.

What you need in order to administer your injection using the Metopen pre-filled pen

You need:

• 1 Metopen pre-filled pen

• 1 alcohol pad

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