Document: leaflet MAH BRAND_PLPI 20636-2529 change

• leaflet MAH BRAND_PLPI 15184-1510
• leaflet MAH BRAND_PLPI 20636-2364
• leaflet MAH BRAND_PLPI 20636-2529

---

PATIENT INFORMATION LEAFLET    2529

25.04.14[5]

Metoject® 50 mg/ml solution for injection

(methotrexate)

Read all of this leaflet carefully before you start using this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, please ask your doctor or pharmacist.

•    This medicine has been prescribed for you. 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.

This medicine is available using above name but will be referred to as Metoject 50 mg/ml throughout the leaflet.

In this leaflet:

1.    What Metoject 50 mg/ml is and what it is used for

2.    What you need to know before you use Metoject 50 mg/ml

3.    How to use Metoject 50 mg/ml

4.    Possible side effects

5.    How to store Metoject 50 mg/ml

6.    Contents of the pack and other information

1.    WHAT METOJECT 50 MG/ML IS AND WHAT IT IS USED FOR

Metoject 50 mg/ml is indicated for the treatment of

•    active rheumatoid arthritis in adult patients.

•    polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.

•    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.

•    mild to moderate Crohn's Disease in adult patients when adequate treatment with other medicines is not possible.

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.

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

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

Metoject 50 mg/ml modifies and slows down the progression of the disease.

Crohn's Disease is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract causing symptoms such as abdominal pain, diarrhoea, vomiting or weight loss.

2.    WHAT YOU NEED TO KNOW BEFORE YOU USE METOJECT 50 MG/ML

Do not use Metoject 50 mg/ml 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, e.g. tuberculosis, HIV or other immunodeficiency syndromes.

•    suffer from 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 Metoject 50 mg/ml if:

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

•    you have problems with the way your liver works.

•    you suffer from dehydration (water loss).

Recommended follow-up examinations and safety measures:

Even when Metoject 50 mg/ml 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 alterations of the mucosa

•    Blood tests

•    Check if your liver is working properly

•    Check if your kidneys are working properly

•    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 (e.g. herpes zoster [shingles], tuberculosis, hepatitis B or C) may flare up. During therapy with Metoject 50 mg/ml 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 therapy must then be stopped.

Diarrhoea can be a toxic effect of Metoject 50 mg/ml and requires an interruption of therapy. If you suffer from diarrhoea please speak to your doctor.

Other medicines and Metoject 50 mg/ml

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The effect of the treatment may be affected if Metoject 50 mg/ml is administered at the same time as certain other drugs:

•    Medicines harming the liver or the blood count, e.g. leflunomide

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

•    Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or inflammation)

•    Probenecid (medicine against gout)

•    Weak organic acids like loop diuretics (“water tablets”) or some medicines used for treatment of pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and ibuprofen) and pyrazole (e.g. metamizol for treating pain)

•    Medicinal products, which may have adverse effects on the bone marrow, e.g. trimethoprim-sulphamethoxazole (an antibiotic) and pyrimethamine

•    Sulphasalazine (antirheumatic medicine)

•    Azathioprine (an immunosuppressive agent sometimes used in severe forms of rheumatoid arthritis)

•    Mercaptopurine (a cytostatic agent)

•    Retinoids (medicine against psoriasis and other dermatological diseases)

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

•    Proton-pump inhibitors (medicines against stomach trouble)

•    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 should be avoided.

Metoject 50 mg/ml 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 Metoject 50 mg/ml.

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.

You must not take Metoject 50 mg/ml during pregnancy. Men and women should use an effective method of birth control during treatment and during a further six months after treatment with Metoject 50 mg/ml has been discontinued.

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. 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, and men should seek advice about the possibility of sperm preservation before starting therapy.

Breast-feeding should be stopped prior to and during treatment with Metoject 50 mg/ml.

Driving and using machines

Treatment with Metoject 50 mg/ml may cause adverse reactions affecting the central nervous system, e.g. 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 you should not drive or use machines.

Important information about some of the ingredients of Metoject 50 mg/ml

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

3.    HOW TO USE METOJECT 50 MG/ML

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

Metoject 50 mg/ml is administered 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. Metoject 50 mg/ml may be injected intramuscularly (in a muscle), intravenously (in a vein) or subcutaneously (under the skin).

As there is very little data about giving the medicine intravenously in children and adolescents, it must only be injected under the skin or into a muscle.

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

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

Method and duration of administration Metoject 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 Metoject is a long-term treatment.

At the start of your therapy, Metoject may be injected by medical staff.

In certain cases your doctor may decide to instruct you how to inject Metoject under the skin yourself. You will then receive appropriate training.

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

Please refer to the instructions for use at the end of the leaflet.

The manner of handling and disposal must be consistent with that of other cytostatic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Metoject 50 mg/ml.

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 have the impression that the effect of Metoject 50 mg/ml is too strong or too weak, you should 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 require urgent specific treatment:

• persistent dry, non-productive cough, shortness of breath and fever; these may be signs of an inflammation of the lungs (pneumonia) [common — may affect up to 1 in 10 people]

*    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 of the liver (liver fibrosis), fatty degeneration of the liver [all uncommon — may affect up to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare - may affect up to 1 in 1,000 people] and liver failure [very rare - may affect up to 1 in

10,000 people]

*    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 - may affect up to 1 in 1,000 people]

*    symptoms of kidney damage such as swelling of the hands, ankles or feet or changes in frequency of urination or decrease or absence of urine; these may be signs of kidney failure [rare - may affect up to 1 in 1,000 people]

*    symptoms of infections, e.g. fever, chills, achiness, sore throat;

methotrexate can make you more susceptible to infections. Rarely [may affect up to 1 in 1,000 people] severe infections like a certain type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis) may occur

*    severe diarrhoea, vomiting blood and black or tarry stools; these symptoms may indicate a rare [may affect up to 1 in 1,000 people] severe complication of the gastrointestinal system caused by methotrexate e.g. gastrointestinal ulcers

*    fever and serious deterioration of your general condition, or sudden fever accompanied by a sore throat or mouth, or urinary problems; methotrexate can very rarely [may affect up to 1 in 10,000 people] cause a sharp fall in white blood cells (agranulocytosis) and severe bone marrow suppression

*    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 - may affect up to 1 in 10,000 people]

*    severe skin rash or blistering of the skin (this can also affect your mouth, eyes and genitals); these may be signs of the very rare [may affect up to 1 in 10,000 people] conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal necrolysis)

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

Very common: may affect more than 1 in 10 people

*    Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite

*    Increase in liver enzymes

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 (leukopenia, anaemia, thrombocytopenia)

Uncommon: may affect up to 1 in 100 people

*    Throat inflammation, inflammation of the bowels, vomiting

*    Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, shingles, inflammation of blood vessels, herpeslike skin rash, hives

*    Onset of diabetes mellitus

*    Dizziness, confusion, depression

*    Decrease in serum albumin

*    Decrease in the number of blood cells and platelets

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

*    Joint pain, muscle pain, osteoporosis (reduction of bone mass)

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

*    Increased skin pigmentation, acne, blue spots due to vessel bleeding

*    Allergic inflammation of blood vessels, fever, red eyes, infection, wound-healing impairment, decreased number of anti-bodies in the blood

*    Visual disturbances

*    Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart

*    Low blood pressure, occlusion of a blood vessel by dislodged blood clot (thromboembolic events)

*    Lung fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the sac around the lung

*    Electrolyte disturbances

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

*    Profuse bleeding, toxic megacolon (acute toxic dilatation of the gut)

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

*    Local damage (formation of sterile abscess, changes in the fatty tissue) of injection site following administration into a muscle or under the skin

*    Impaired vision, pain, loss of strength or sensation of numbness or tingling in arms and legs, changes in taste (metallic taste), convulsions, paralysis, severe headache with fever

*    Retinopathy (noninflammatory eye disorder)

*    Loss of sexual drive, impotence, male breast enlargement (gynaecomastia), defective sperm formation, menstrual disorder,

*    vaginal discharge

*    Enlargement of lymphatic nodes (lymphoma)

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated.

Only mild local skin reactions were observed, decreasing during therapy.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Metoject 50 mg/ml

Keep out of the sight and reach of children.

Do not store above 25 °C.

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

Do not use after the expiry date stated on the packaging. The expiry date refers to the last day of that month.

Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required.

The measures will help to protect the environment

6. Further information

What Metoject 50 mg/ml contains

*    The active substance is methotrexate.

1 ml of solution contains 50 mg methotrexate as (methotrexate disodium).

1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10 mg methotrexate.

1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15 mg methotrexate.

1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20 mg methotrexate.

1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25 mg methotrexate.

*    The other ingredients are sodium chloride, sodium hydroxide, water for injections.

What Metoject 50 mg/ml looks like and contents of the pack

A pre-filled colourless glass syringe of 1 ml capacity, filled with a clear, yellow-brown solution. It is embedded with an injection needle with a plunger stopper of rubber and plastic rods inserted on the stopper to form the syringe. Also contains alcohol pads.

The following pack sizes are available:

Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 m and 0.50 ml of solution are available in a packsize of 1 syringe with embedded SC needle.

Alcohol pads included in the package.

Product Licence Holder and Manufacturer

Manufactured by medac Gesellschaft fur klinische Spezialpraparate mbH, Theaterstr. 6, 22880 Wedel, Germany and procured from the EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow, Middlesex HA1 1XD. Repackaged by Servipharm Ltd.

Leaflet issue and revision date (Ref): 25.04.14[5]

Metoject is trademark of medac Gesellschaft fur klinische Spezialpraparate mbH.

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

Austria, Belgium, Bulgaria, Czech Republic, Finland, Greece, Hungary, Iceland, Netherlands, Romania, Slovak Republic, Slovenia, Spain, Sweden, United Kingdom: Metoject

Denmark, Estonia, Latvia, Lithuania, Norway, Poland and Portugal: Metex

Germany: metex Italy: Reumaflex

Instructions for use

Carefully read the instructions below before starting your injection, and always use the injection technique advised by your doctor, pharmacist or nurse.

For any problem or question, contact your doctor, pharmacist or nurse.

Preparation

Select a clean, well-lit and flat working surface.

Collect necessary items before you begin:

*    1 Metoject pre-filled syringe

*    1 alcohol pad (provided in the packaging)

Wash your hands carefully. Before use, check the Metoject syringe for visual defects (or cracks).

Injection site

Areas for subcutaneous injection

The best sites for injection are:

-    upper thighs,

-    abdomen except around the navel.

*    If someone is helping you with the injection, he/ she may also give the injection into the back of your arms, just below the shoulder.

*    Change the injection site with each injection.

This may reduce the risk of developing irritations at the injection site.

*    Never inject into skin that is tender, bruised, red, hard, scarred or where you have stretch marks.

If you have psoriasis, you should try not to inject directly into any raised, thick, red or scaly skin patches or lesions.

Injecting the solution

1. Unpack the methotrexate pre-filled syringe and read the package leaflet carefully. Remove the pre-filled syringe from the packaging at room temperature.

2. Disinfection

Choose an injection site and disinfect it with a swab soaked in disinfectant.

Allow at least 60 seconds for the disinfectant to dry.

3. Remove the protective plastic cap

Carefully remove the grey protective plastic cap by pulling it straight off the syringe. If the cap is very stiff, turn it slightly with a pulling movement.

Important: Do not touch the needle of the prefilled syringe!

4. Inserting the cannula

Using two fingers, pinch up a fold of skin and quickly insert the needle into the skin at a 90-degree angle.

5. Injection

Insert the needle fully into the fold of skin. Push the plunger down slowly and inject the liquid underneath your skin. Hold the skin securely until the injection is completed. Carefully pull the needle straight out.

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 or someone around you is injured by the needle, consult your doctor immediately and do not use this pre-filled syringe.

Disposal and other handling

The manner of handling and throwing away of the medicine and prefilled syringe must be in accordance with local requirements. Pregnant healthcare personnel should not handle and/or administer Metoject.

SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

Metoject 50 mg/ml solution for injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

-    1 ml of solution contains 50 mg methotrexate as (methotrexate disodium).

1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10 mg methotrexate.

1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15 mg methotrexate.

1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20 mg methotrexate.

1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25 mg methotrexate.

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Solution for injection, in pre-filled syringe.

Clear, yellow-brown solution.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metoject 50 mg/ml is indicated for the treatment of

-    active rheumatoid arthritis in adult patients,

-    polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,

-    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.

-    mild to moderate Crohn's disease either alone or in combination with corticosteroids in adult patients refractory or intolerant to thiopurines.

4.2    Posology and method of administration

Metoject 50 mg/ml should only be prescribed by physicians, who are familiar with the various characteristics of the medicinal product and its mode of action. The administration should routinely be done by health professionals. If the clinical situation permits the treating physician can, in selected cases, delegate the subcutaneous administration to the patient her/himself. In these cases, detailed administration instructions from the physician are obligate. Metoject 50 mg/ml is injected once weekly.

The patient is to be explicitly informed about the fact of administration once weekly. It is advisable to determine a fixed, appropriate weekday as day of injection.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).

Dosage in adult patients with rheumatoid arthritis:

The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. Depending on the individual activity of the disease and tolerability by the patient, the initial dose may be increased gradually by 2.5 mg per week. A weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg/week are associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4 - 8 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis

The recommended dose is 10-15 mg/m² body surface area (BSA)/once weekly. In therapy-refractory cases the weekly dosage may be increased up to 20mg/m² body surface area/once weekly. However, an increased monitoring frequency is indicated if the dose is increased. Due to limited data availability about intravenous use in children and adolescents, parenteral administration is limited to subcutaneous and intramuscular injection.

Patients with JIA should always be referred to a rheumatology specialist in the treatment of children/adolescents.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population. (see section 4.4)

Dosage in patients with psoriasis vulgaris and psoriatic arthritis:

It is recommended that a test dose of 5 - 10 mg should be administered parenterally, one week prior to therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can generally be expected after approximately 2 - 6 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

The dose should be increased as necessary but should in general not exceed the maximum recommended weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Dosage in patients with Crohn's Disease:

-    Induction treatment:

25 mg/week administered either subcutaneously, intravenously or intramuscularly.

Response to treatment can be expected after approximately 8 to 12 weeks.

-    Maintenance treatment:

15mg/week administered either subcutaneously, intravenously or intramuscularly.

There is not sufficient experience in the paediatric population to recommend Metoject 50 mg/ml for the treatment of Crohn's Disease in this population.

Patients with renal impairment:

Metoject 50 mg/ml should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:

Creatinine clearance (ml/min) Dose > 50    100 %

20 - 50    50 %

< 20    Metoject 50 mg/ml must not be used

See section 4.3

Patients with hepatic impairment:

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. If bilirubin is > 5 mg/dl (85.5 gmol/l), methotrexate is contraindicated.

For a full list of contraindications, see section 4.3.

Use in elderly patients:

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Use in patient with a third distribution space (pleural effusions, ascitis):

As the half-life of Methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see section 5.2 and 4.4).

Duration and method of administration:

The medicine is for single use only.

Metoject 50 mg/ml solution for injection can be given by intramuscular, intravenous or subcutaneous route (in children and adolescents only subcutaneous or intramuscular).

The overall duration of the treatment is decided by the physician.

Note:

If changing from oral to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration.

Folic acid supplementation may be considered according to current treatment guidelines.

4.3 Contraindications

Metoject 50 mg/ml is contraindicated in the case of

-    hypersensitivity to methotrexate or to any of the excipients,

-    severe liver impairment (see section 4.2),

-    alcohol abuse,

-    severe renal impairment (creatinine clearance less than 20 ml/min., see section 4.2 and section 4.4),

-    pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia,

-    serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,

-    ulcers of the oral cavity and known active gastrointestinal ulcer disease,

-    pregnancy, breast-feeding (see section 4.6),

-    concurrent vaccination with live vaccines.

4.4 Special warnings and precautions for use

Patients must be clearly informed that the therapy has to be applicated once a week, not every day.

Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Therefore methotrexate should be only administered by, or under the supervision of physicians whose knowledge and experience includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic reactions, the patient should be fully informed by the physician of the risks involved and the recommended safety measures.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population (see section 4.2).

Recommended examinations and safety measures

Before beginning or reinstituting methotrexate therapy after a rest period: Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy (at least once a month during the first six months and every three months thereafter):

An increased monitoring frequency should be considered also when the dose is increased.

1.    Examination of the mouth and throat for mucosal changes

2.    Complete blood count with differential blood count and platelets. Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white-cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy. Patients should be advised to report all signs and symptoms suggestive of infection. Patients taking simultaneous administration of haematotoxic medicinal products (e.g. leflunomide) should be monitored closely with blood count and platelets.

3.    Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications.

For psoriasis patients the need for a liver biopsy prior to and during therapy is controversial. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and differentiate between patients with no risk factors and patients with risk factors such as excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to hepatotoxic drugs or chemicals and prolonged Methotrexate treatment or cumulative doses of 1.5 g or more.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13 - 20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide).

4.    Renal function should be monitored by renal function tests and urinanalysis (see sections 4.2 and 4.3).

As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be expected in the case of renal impairment, which may result in severe undesirable effects.

Where renal function may be compromised (e.g. in the elderly), monitoring should take place more frequently. This applies in particular, when medicinal products are administered concomitantly, which affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal anti-inflammatory medicinal products) or which can potentially lead to impairment of blood formation. Dehydration may also intensify the toxicity of methotrexate.

5.    Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be excluded. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate therapy. This lesion can occur at all dosages.

6.    Methotrexate may, due to its effect on the immune system, impair the response to vaccination results and affect the result of immunological tests. Particular caution is also needed in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of eventual activation. Vaccination using live vaccines must not be carried out under methotrexate therapy.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

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.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment (see section 5.2).

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium-free".

The absence of pregnancy should be confirmed before Metoject 50 mg/ml is administered. Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Methotrexate affects spermatogenesis and oogenesis during the period of its administration which may result in decreased fertility. These effects appear to be reversible on discontinuing therapy. Effective contraception in men and women should be performed during treatment and for at least six months thereafter. The possible risks of effects on reproduction should be discussed with patients of childbearing potential and their partners should be advised appropriately (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4).

Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be monitored with special care. The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine). The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with methotrexate.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of hepatotoxicity.

Oral antibiotics

Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the bacterial metabolism.

Antibiotics

Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

Medicinal products with high plasma protein binding Methotrexate is plasma protein bound and may be displaced by other protein bound drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal antiinflammatory agents

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed inducing higher haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate and non steroidal anti-inflammatory medicinal products or salicylates are combined.

Medicinal products with adverse reactions on the bone marrow In the case of medication with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation.

Medicinal products which cause folate deficiency

The concomitant administration of products which cause folate deficiency (e.g. sulphonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency.

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when Metoject 50 mg/ml is administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, sulphasalazine, azathioprine, ciclosporin).

Sulphasalazine

Although the combination of methotrexate and sulphasalazine can cause an increase in efficacy of methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through sulphasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Caffeine- or theophylline-containing beverages An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing soft drinks, black tea) should be avoided during methotrexate therapy.

4.6    Fertility, pregnancy and lactation

Pregnancy

Metoject 50 mg/ml is contraindicated during pregnancy (see section 4.3). In animal studies, methotrexate has shown reproductive toxicity (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death and/or congenital abnormalities. Exposure of a limited number of pregnant women (42) resulted in an increased incidence (1:14) of malformations (cranial, cardiovascular and extremital). If methotrexate is discontinued prior to conception, normal pregnancies have been reported. Women must not get pregnant during methotrexate therapy. In case of women getting pregnant during therapy medical counselling about the risk of adverse reactions for the child associated with methotrexate therapy should be sought. Therefore, patients of a sexually mature age (women and men) must use effective contraception during treatment with Metoject 50 mg/ml and at least 6 months thereafter (see section 4.4).

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

Breast-feeding

Methotrexate is excreted in breast milk in such concentrations that there is a risk for the infant, and accordingly, breast-feeding should be discontinued prior to and throughout administration.

Fertility

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, and men should seek advice about the possibility of sperm preservation before starting therapy.

4.7    Effects on ability to drive and use machines

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metoject 50 mg/ml has minor or moderate influence on the ability to drive and use machines.

4.8    Undesirable effects

The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal disorders.

The following headings are used to organise the undesirable effects in order of frequency:

Very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)

Neoplasms benign, malignant and unspecified (including cysts and

polyps)

Very rare: There have been reports of individual cases of lymphoma which subsided in a number of cases once treatment with methotrexate had been discontinued. In a recent study, it could not be established that methotrexate therapy increases the incidence of lymphomas.

Blood and lymphatic system disorders Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression.

Metabolism and nutrition disorders Uncommon: Precipitation of diabetes mellitus.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness, confusion, depression.

Very rare: Impaired vision, pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste), convulsions, meningism, paralysis.

Eye disorders

Rare: Visual disturbances.

Very rare: Retinopathy.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of breath and fever.

Rare: Pulmonary fibrosis, Pneumocystis carinii pneumonia, shortness of breath and bronchial asthma, pleural effusion.

Gastrointestinal disorders

Very common: Stomatitis, dyspepsia, nausea, loss of appetite.

Common: Oral ulcers, diarrhoea.

Uncommon: Pharyngitis, enteritis, vomiting.

Rare: Gastrointestinal ulcers.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Hepatobiliary disorders (see section 4.4)

Very common: Elevated transaminases.

Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Skin and subcutaneous tissue disorders Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria.

Rare: Increased pigmentation, acne, ecchymosis.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

Musculoskeletal and connective tissue disorders Uncommon: Arthralgia, myalgia, osteoporosis.

Renal and urinary disorders

Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare: Renal failure, oliguria, anuria, electrolyte disturbances.

Reproductive system and breast disorders Uncommon: Inflammation and ulceration of the vagina.

Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge.

General disorders and administration site conditions

Rare: Allergic reactions, anaphylactic shock, allergic vasculitis, fever,

conjunctivitis, infection, sepsis, wound-healing impairment,

hypogammaglobulinaemia.

Very rare: Local damage (formation of sterile abscess, lipodystrophy) of injection site following intramuscular or subcutaneous administration.

The appearance and degree of severity of undesirable effects depends on the dosage level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals.

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated.

Only mild local skin reactions were observed, decreasing during therapy.

4.9 Overdose

a)    Symptoms of overdosage

Toxicity of methotrexate mainly affects the haematopoietic system.

b)    Treatment measures in the case of overdosage

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within one hour and dosing continued until the serum levels of methotrexate are below 10^-7 mol/l.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Folic acid analogues ATC code: L01BA01

Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for the treatment of Crohn's disease.

Mechanism of action

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriasis arthritis, chronic polyarthritis and Crohn's disease, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects.

International clinical guidelines reflect the use of methotrexate as a second choice for Crohn's disease patients that are intolerant or have failed to respond to first-line immunomodulating agents as azathioprine (AZA) or 6-mercaptopurine (6-MP).

The adverse events observed in the studies performed with methotrexate for Crohn's disease at cumulative doses have not shown a different safety profile of methotrexate than the profile it is already known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of Crohn's disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4 and 4.6).

5.2    Pharmacokinetic properties

Distribution

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are possible (25 - 100 %). Maximum serum concentrations are achieved after 1 - 2 hours.

Biotransformation

Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.

Elimination

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in particular, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts.

The terminal half-life is on average 6 - 7 hours and demonstrates considerable variation (3 - 17 hours). The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution space (pleural effusion, ascites).

Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle metabolite is 7-hydroxymethotrexate. Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus. Approx.

5 - 20 % methotrexate and 1 - 5 % 7-hydroxymethotrexate are eliminated biliary. There is pronounced enterohepatic circulation.

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to hepatic impairment is not known.

5.3 Preclinical safety data

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered not classifiable as to its carcinogenicity to humans.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium chloride

Sodium hydroxide for pH adjustment Water for injections

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf-life

2 years.

6.4    Special precautions for storage

Do not store above 25 °C. Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5    Nature and contents of container

Nature of container:

A pre-filled colourless glass syringe of 1 ml capacity, filled with a clear, yellow-brown solution. It is embedded with an injection needle with a plunger stopper of rubber and plastic rods inserted on the stopper to form the syringe. Also contains alcohol pads.

Pack sizes:

The following pack sizes are available:

Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 m and 0.50 ml of solution are available in a packsize of 1 syringe with embedded SC needle. Alcohol pads included in the package.

All pack sizes are available with graduation marks.

6.6    Special precautions for disposal and other handling

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Metoject 50 mg/ml.

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

For single use only.

Any unused product or waste should be disposed of in accordance with local requirements.

Instructions for subcutaneous use

The best places for the injection are:

-    upper thighs,

-    abdomen except around the navel.

1. Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad).

2.    Pull the protective plastic cap straight off.

3. Build a skin fold by gently squeezing the area at the injection site.

4. The fold must be held pinched until the syringe is removed from the skin after the injection.

5. Push the needle fully into the skin at a 90-degree angle.

6.    Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from the skin at the same 90-degree angle.

7.    MARKETING AUTHORISATION HOLDER

Procured from the EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow, Middlesex HA1 1XD. Repackaged by Servipharm Ltd.

8.    MARKETING AUTHORISATION NUMBER

PL 20636/2529

9.    DATE OF REVISION OF THE TEXT 25.04.14[S-5]

PATIENT INFORMATION LEAFLET    2529

25.04.14[5]

Metex® 50 mg/ml solution for injection

(methotrexate)

Read all of this leaflet carefully before you start using this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, please ask your doctor or pharmacist.

•    This medicine has been prescribed for you. 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.

This medicine is available using above name but will be referred to as Metex 50 mg/ml 50 mg/ml throughout the leaflet.

In this leaflet:

1.    What Metex 50 mg/ml is and what it is used for

2.    What you need to know before you use Metex 50 mg/ml

3.    How to use Metex 50 mg/ml

4.    Possible side effects

5.    How to store Metex 50 mg/ml

6.    Contents of the pack and other information

1.    WHAT METEX 50 MG/ML IS AND WHAT IT IS USED FOR

Metex 50 mg/ml is indicated for the treatment of

•    active rheumatoid arthritis in adult patients.

•    polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.

•    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.

•    mild to moderate Crohn's Disease in adult patients when adequate treatment with other medicines is not possible.

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.

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

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

Metex 50 mg/ml modifies and slows down the progression of the disease.

Crohn's Disease is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract causing symptoms such as abdominal pain, diarrhoea, vomiting or weight loss.

2.    WHAT YOU NEED TO KNOW BEFORE YOU USE METEX 50 MG/ML

Do not use Metex 50 mg/ml 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, e.g. tuberculosis, HIV or other immunodeficiency syndromes.

•    suffer from 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 Metex 50 mg/ml if:

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

•    you have problems with the way your liver works.

•    you suffer from dehydration (water loss).

Recommended follow-up examinations and safety measures:

Even when Metex 50 mg/ml 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 alterations of the mucosa

•    Blood tests

•    Check if your liver is working properly

•    Check if your kidneys are working properly

•    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 (e.g. herpes zoster [shingles], tuberculosis, hepatitis B or C) may flare up. During therapy with Metex 50 mg/ml 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 therapy must then be stopped.

Diarrhoea can be a toxic effect of Metex 50 mg/ml and requires an interruption of therapy. If you suffer from diarrhoea please speak to your doctor.

Other medicines and Metex 50 mg/ml

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The effect of the treatment may be affected if Metex 50 mg/ml is administered at the same time as certain other drugs:

•    Medicines harming the liver or the blood count, e.g. leflunomide

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

•    Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or inflammation)

•    Probenecid (medicine against gout)

•    Weak organic acids like loop diuretics (“water tablets”) or some medicines used for treatment of pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and ibuprofen) and pyrazole (e.g. metamizol for treating pain)

•    Medicinal products, which may have adverse effects on the bone marrow, e.g. trimethoprim-sulphamethoxazole (an antibiotic) and pyrimethamine

•    Sulphasalazine (antirheumatic medicine)

•    Azathioprine (an immunosuppressive agent sometimes used in severe forms of rheumatoid arthritis)

•    Mercaptopurine (a cytostatic agent)

•    Retinoids (medicine against psoriasis and other dermatological diseases)

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

•    Proton-pump inhibitors (medicines against stomach trouble)

•    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 should be avoided.

Metex 50 mg/ml 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 Metex 50 mg/ml.

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.

You must not take Metex 50 mg/ml during pregnancy. Men and women should use an effective method of birth control during treatment and during a further six months after treatment with Metex 50 mg/ml has been discontinued.

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. 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, and men should seek advice about the possibility of sperm preservation before starting therapy.

Breast-feeding should be stopped prior to and during treatment with Metex 50 mg/ml.

Driving and using machines

Treatment with Metex 50 mg/ml may cause adverse reactions affecting the central nervous system, e.g. 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 you should not drive or use machines.

Important information about some of the ingredients of Metex 50 mg/ml

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

3.    HOW TO USE METEX 50 MG/ML

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

Metex 50 mg/ml is administered 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. Metex 50 mg/ml may be injected intramuscularly (in a muscle), intravenously (in a vein) or subcutaneously (under the skin).

As there is very little data about giving the medicine intravenously in children and adolescents, it must only be injected under the skin or into a muscle.

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

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

Method and duration of administration Metex 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 Metex is a long-term treatment.

At the start of your therapy, Metex may be injected by medical staff.

In certain cases your doctor may decide to instruct you how to inject Metex under the skin yourself. You will then receive appropriate training. Under no circumstances should you try to inject Metex yourself before you have received such training.

Please refer to the instructions for use at the end of the leaflet.

The manner of handling and disposal must be consistent with that of other cytostatic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Metex 50 mg/ml.

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 have the impression that the effect of Metex 50 mg/ml is too strong or too weak, you should 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 require urgent specific treatment:

• persistent dry, non-productive cough, shortness of breath and fever; these may be signs of an inflammation of the lungs (pneumonia) [common — may affect up to 1 in 10 people]

*    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 of the liver (liver fibrosis), fatty degeneration of the liver [all uncommon — may affect up to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare - may affect up to 1 in 1,000 people] and liver failure [very rare - may affect up to 1 in

10,000 people]

*    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 - may affect up to 1 in 1,000 people]

*    symptoms of kidney damage such as swelling of the hands, ankles or feet or changes in frequency of urination or decrease or absence of urine; these may be signs of kidney failure [rare - may affect up to 1 in 1,000 people]

*    symptoms of infections, e.g. fever, chills, achiness, sore throat;

methotrexate can make you more susceptible to infections. Rarely [may affect up to 1 in 1,000 people] severe infections like a certain type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis) may occur

*    severe diarrhoea, vomiting blood and black or tarry stools; these symptoms may indicate a rare [may affect up to 1 in 1,000 people] severe complication of the gastrointestinal system caused by methotrexate e.g. gastrointestinal ulcers

*    fever and serious deterioration of your general condition, or sudden fever accompanied by a sore throat or mouth, or urinary problems; methotrexate can very rarely [may affect up to 1 in 10,000 people] cause a sharp fall in white blood cells (agranulocytosis) and severe bone marrow suppression

*    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 - may affect up to 1 in 10,000 people]

*    severe skin rash or blistering of the skin (this can also affect your mouth, eyes and genitals); these may be signs of the very rare [may affect up to 1 in 10,000 people] conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal necrolysis)

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

Very common: may affect more than 1 in 10 people

*    Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite

*    Increase in liver enzymes

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 (leukopenia, anaemia, thrombocytopenia)

Uncommon: may affect up to 1 in 100 people

*    Throat inflammation, inflammation of the bowels, vomiting

*    Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, shingles, inflammation of blood vessels, herpeslike skin rash, hives

*    Onset of diabetes mellitus

*    Dizziness, confusion, depression

*    Decrease in serum albumin

*    Decrease in the number of blood cells and platelets

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

*    Joint pain, muscle pain, osteoporosis (reduction of bone mass)

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

*    Increased skin pigmentation, acne, blue spots due to vessel bleeding

*    Allergic inflammation of blood vessels, fever, red eyes, infection, wound-healing impairment, decreased number of anti-bodies in the blood

*    Visual disturbances

*    Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart

*    Low blood pressure, occlusion of a blood vessel by dislodged blood clot (thromboembolic events)

*    Lung fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the sac around the lung

*    Electrolyte disturbances

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

*    Profuse bleeding, toxic megacolon (acute toxic dilatation of the gut)

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

*    Local damage (formation of sterile abscess, changes in the fatty tissue) of injection site following administration into a muscle or under the skin

*    Impaired vision, pain, loss of strength or sensation of numbness or tingling in arms and legs, changes in taste (metallic taste), convulsions, paralysis, severe headache with fever

*    Retinopathy (noninflammatory eye disorder)

*    Loss of sexual drive, impotence, male breast enlargement (gynaecomastia), defective sperm formation, menstrual disorder,

*    vaginal discharge

*    Enlargement of lymphatic nodes (lymphoma)

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated.

Only mild local skin reactions were observed, decreasing during therapy.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Metex 50 mg/ml

Keep out of the sight and reach of children.

Do not store above 25 °C.

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

Do not use after the expiry date stated on the packaging. The expiry date refers to the last day of that month.

Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required.

The measures will help to protect the environment

6. Further information What Metex 50 mg/ml contains

*    The active substance is methotrexate.

1 ml of solution contains 50 mg methotrexate as (methotrexate disodium).

1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10 mg methotrexate.

1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15 mg methotrexate.

1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20 mg methotrexate.

1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25 mg methotrexate.

*    The other ingredients are sodium chloride, sodium hydroxide, water for injections.

What Metex 50 mg/ml looks like and contents of the pack

A pre-filled colourless glass syringe of 1 ml capacity, filled with a clear, yellow-brown solution. It is embedded with an injection needle with a plunger stopper of rubber and plastic rods inserted on the stopper to form the syringe. Also contains alcohol pads.

The following pack sizes are available:

Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 m and 0.50 ml of solution are available in a packsize of 1 syringe with embedded SC needle.

Alcohol pads included in the package.

Product Licence Holder and Manufacturer

Manufactured by medac Gesellschaft fur klinische Spezialpraparate mbH, Theaterstr. 6, 22880 Wedel, Germany and procured from the EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow, Middlesex HA1 1XD. Repackaged by Servipharm Ltd.

Leaflet issue and revision date (Ref): 25.04.14[5]

Metex is a registered trademark.

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

Austria, Belgium, Bulgaria, Czech Republic, Finland, Greece, Hungary, Iceland, Netherlands, Romania, Slovak Republic, Slovenia, Spain, Sweden, United Kingdom: Metoject

Denmark, Estonia, Latvia, Lithuania, Norway, Poland and Portugal: Metex

Germany: metex Italy: Reumaflex

Instructions for use

Carefully read the instructions below before starting your injection, and always use the injection technique advised by your doctor, pharmacist or nurse.

For any problem or question, contact your doctor, pharmacist or nurse. Preparation

Select a clean, well-lit and flat working surface.

Collect necessary items before you begin:

*    1 Metex pre-filled syringe

*    1 alcohol pad (provided in the packaging)

Wash your hands carefully. Before use, check the Metex syringe for visual defects (or cracks).

Injection site

Areas for subcutaneous injection

The best sites for injection are:

-    upper thighs,

-    abdomen except around the navel.

*    If someone is helping you with the injection, he/ she may also give the injection into the back of your arms, just below the shoulder.

*    Change the injection site with each injection.

This may reduce the risk of developing irritations at the injection site.

*    Never inject into skin that is tender, bruised, red, hard, scarred or where you have stretch marks.

If you have psoriasis, you should try not to inject directly into any raised, thick, red or scaly skin patches or lesions.

Injecting the solution

1. Unpack the methotrexate pre-filled syringe and read the package leaflet carefully. Remove the pre-filled syringe from the packaging at room temperature.

2. Disinfection

Choose an injection site and disinfect it with a swab soaked in disinfectant.

Allow at least 60 seconds for the disinfectant to dry.

3. Remove the protective plastic cap

Carefully remove the grey protective plastic cap by pulling it straight off the syringe. If the cap is very stiff, turn it slightly with a pulling movement.

Important: Do not touch the needle of the prefilled syringe!

4. Inserting the cannula

Using two fingers, pinch up a fold of skin and quickly insert the needle into the skin at a 90-degree angle.

5. Injection

Insert the needle fully into the fold of skin. Push the plunger down slowly and inject the liquid underneath your skin. Hold the skin securely until the injection is completed. Carefully pull the needle straight out.

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 or someone around you is injured by the needle, consult your doctor immediately and do not use this pre-filled syringe.

Disposal and other handling

The manner of handling and throwing away of the medicine and prefilled syringe must be in accordance with local requirements. Pregnant healthcare personnel should not handle and/or administer Metex.

SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

Metex 50 mg/ml solution for injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

-    1 ml of solution contains 50 mg methotrexate as (methotrexate disodium).

1 syringe (0.20 ml) contains methotrexate disodium equivalent to 10 mg methotrexate.

1 syringe (0.30 ml) contains methotrexate disodium equivalent to 15 mg methotrexate.

1 syringe (0.40 ml) contains methotrexate disodium equivalent to 20 mg methotrexate.

1 syringe (0.50 ml) contains methotrexate disodium equivalent to 25 mg methotrexate.

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Solution for injection, in pre-filled syringe.

Clear, yellow-brown solution.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metex 50 mg/ml is indicated for the treatment of

-    active rheumatoid arthritis in adult patients,

-    polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate,

-    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.

-    mild to moderate Crohn's disease either alone or in combination with corticosteroids in adult patients refractory or intolerant to thiopurines.

4.2    Posology and method of administration

Metex 50 mg/ml should only be prescribed by physicians, who are familiar with the various characteristics of the medicinal product and its mode of action. The administration should routinely be done by health professionals. If the clinical situation permits the treating physician can, in selected cases, delegate the subcutaneous administration to the patient her/himself. In these cases, detailed administration instructions from the physician are obligate. Metex 50 mg/ml is injected once weekly.

The patient is to be explicitly informed about the fact of administration once weekly. It is advisable to determine a fixed, appropriate weekday as day of injection.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).

Dosage in adult patients with rheumatoid arthritis:

The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. Depending on the individual activity of the disease and tolerability by the patient, the initial dose may be increased gradually by 2.5 mg per week. A weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg/week are associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4 - 8 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis

The recommended dose is 10-15 mg/m² body surface area (BSA)/once weekly. In therapy-refractory cases the weekly dosage may be increased up to 20mg/m² body surface area/once weekly. However, an increased monitoring frequency is indicated if the dose is increased. Due to limited data availability about intravenous use in children and adolescents, parenteral administration is limited to subcutaneous and intramuscular injection.

Patients with JIA should always be referred to a rheumatology specialist in the treatment of children/adolescents.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population. (see section 4.4)

Dosage in patients with psoriasis vulgaris and psoriatic arthritis:

It is recommended that a test dose of 5 - 10 mg should be administered parenterally, one week prior to therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either subcutaneously, intramuscularly or intravenously. The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can generally be expected after approximately 2 - 6 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.

The dose should be increased as necessary but should in general not exceed the maximum recommended weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.

Dosage in patients with Crohn's Disease:

-    Induction treatment:

25 mg/week administered either subcutaneously, intravenously or intramuscularly.

Response to treatment can be expected after approximately 8 to 12 weeks.

-    Maintenance treatment:

15mg/week administered either subcutaneously, intravenously or intramuscularly.

There is not sufficient experience in the paediatric population to recommend Metex 50 mg/ml for the treatment of Crohn's Disease in this population.

Patients with renal impairment:

Metex 50 mg/ml should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:

Creatinine clearance (ml/min) Dose > 50    100 %

20 - 50    50 %

< 20    Metex 50 mg/ml must not be used

See section 4.3

Patients with hepatic impairment:

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. If bilirubin is > 5 mg/dl (85.5 gmol/l), methotrexate is contraindicated.

For a full list of contraindications, see section 4.3.

Use in elderly patients:

Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Use in patient with a third distribution space (pleural effusions, ascitis):

As the half-life of Methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see section 5.2 and 4.4).

Duration and method of administration:

The medicine is for single use only.

Metex 50 mg/ml solution for injection can be given by intramuscular, intravenous or subcutaneous route (in children and adolescents only subcutaneous or intramuscular).

The overall duration of the treatment is decided by the physician.

Note:

If changing from oral to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration.

Folic acid supplementation may be considered according to current treatment guidelines.

4.3 Contraindications

Metex 50 mg/ml is contraindicated in the case of

-    hypersensitivity to methotrexate or to any of the excipients,

-    severe liver impairment (see section 4.2),

-    alcohol abuse,

-    severe renal impairment (creatinine clearance less than 20 ml/min., see section 4.2 and section 4.4),

-    pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia,

-    serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,

-    ulcers of the oral cavity and known active gastrointestinal ulcer disease,

-    pregnancy, breast-feeding (see section 4.6),

-    concurrent vaccination with live vaccines.

4.4 Special warnings and precautions for use

Patients must be clearly informed that the therapy has to be applicated once a week, not every day.

Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Therefore methotrexate should be only administered by, or under the supervision of physicians whose knowledge and experience includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic reactions, the patient should be fully informed by the physician of the risks involved and the recommended safety measures.

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population (see section 4.2).

Recommended examinations and safety measures

Before beginning or reinstituting methotrexate therapy after a rest period: Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.

During therapy (at least once a month during the first six months and every three months thereafter):

An increased monitoring frequency should be considered also when the dose is increased.

1.    Examination of the mouth and throat for mucosal changes

2.    Complete blood count with differential blood count and platelets. Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white-cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy. Patients should be advised to report all signs and symptoms suggestive of infection. Patients taking simultaneous administration of haematotoxic medicinal products (e.g. leflunomide) should be monitored closely with blood count and platelets.

3.    Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications.

For psoriasis patients the need for a liver biopsy prior to and during therapy is controversial. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and differentiate between patients with no risk factors and patients with risk factors such as excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to hepatotoxic drugs or chemicals and prolonged Methotrexate treatment or cumulative doses of 1.5 g or more.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13 - 20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide).

4.    Renal function should be monitored by renal function tests and urinanalysis (see sections 4.2 and 4.3).

As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be expected in the case of renal impairment, which may result in severe undesirable effects.

Where renal function may be compromised (e.g. in the elderly), monitoring should take place more frequently. This applies in particular, when medicinal products are administered concomitantly, which affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal anti-inflammatory medicinal products) or which can potentially lead to impairment of blood formation. Dehydration may also intensify the toxicity of methotrexate.

5.    Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be excluded. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate therapy. This lesion can occur at all dosages.

6.    Methotrexate may, due to its effect on the immune system, impair the response to vaccination results and affect the result of immunological tests. Particular caution is also needed in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of eventual activation. Vaccination using live vaccines must not be carried out under methotrexate therapy.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

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.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment (see section 5.2).

Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially "sodium-free".

The absence of pregnancy should be confirmed before Metex 50 mg/ml is administered. Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Methotrexate affects spermatogenesis and oogenesis during the period of its administration which may result in decreased fertility. These effects appear to be reversible on discontinuing therapy. Effective contraception in men and women should be performed during treatment and for at least six months thereafter. The possible risks of effects on reproduction should be discussed with patients of childbearing potential and their partners should be advised appropriately (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4).

Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be monitored with special care. The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine). The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with methotrexate.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of hepatotoxicity.

Oral antibiotics

Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the bacterial metabolism.

Antibiotics

Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

Medicinal products with high plasma protein binding Methotrexate is plasma protein bound and may be displaced by other protein bound drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal antiinflammatory agents

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed inducing higher haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate and non steroidal anti-inflammatory medicinal products or salicylates are combined.

Medicinal products with adverse reactions on the bone marrow In the case of medication with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation.

Medicinal products which cause folate deficiency

The concomitant administration of products which cause folate deficiency (e.g. sulphonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency.

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when Metex 50 mg/ml is administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, sulphasalazine, azathioprine, ciclosporin). Sulphasalazine

Although the combination of methotrexate and sulphasalazine can cause an increase in efficacy of methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through sulphasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Caffeine- or theophylline-containing beverages An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing soft drinks, black tea) should be avoided during methotrexate therapy.

4.6    Fertility, pregnancy and lactation

Pregnancy

Metex 50 mg/ml is contraindicated during pregnancy (see section 4.3).

In animal studies, methotrexate has shown reproductive toxicity (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death and/or congenital abnormalities. Exposure of a limited number of pregnant women (42) resulted in an increased incidence (1:14) of malformations (cranial, cardiovascular and extremital). If methotrexate is discontinued prior to conception, normal pregnancies have been reported. Women must not get pregnant during methotrexate therapy. In case of women getting pregnant during therapy medical counselling about the risk of adverse reactions for the child associated with methotrexate therapy should be sought. Therefore, patients of a sexually mature age (women and men) must use effective contraception during treatment with Metex 50 mg/ml and at least 6 months thereafter (see section 4.4).

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

Breast-feeding

Methotrexate is excreted in breast milk in such concentrations that there is a risk for the infant, and accordingly, breast-feeding should be discontinued prior to and throughout administration.

Fertility

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, and men should seek advice about the possibility of sperm preservation before starting therapy.

4.7    Effects on ability to drive and use machines

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metex 50 mg/ml has minor or moderate influence on the ability to drive and use machines.

4.8    Undesirable effects

The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal disorders.

The following headings are used to organise the undesirable effects in order of frequency:

Very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)

Neoplasms benign, malignant and unspecified (including cysts and

polyps)

Very rare: There have been reports of individual cases of lymphoma which subsided in a number of cases once treatment with methotrexate had been discontinued. In a recent study, it could not be established that methotrexate therapy increases the incidence of lymphomas.

Blood and lymphatic system disorders Common: Leukopenia, anaemia, thrombopenia.

Uncommon: Pancytopenia.

Very rare: Agranulocytosis, severe courses of bone marrow depression.

Metabolism and nutrition disorders Uncommon: Precipitation of diabetes mellitus.

Nervous system disorders

Common: Headache, tiredness, drowsiness.

Uncommon: Dizziness, confusion, depression.

Very rare: Impaired vision, pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste), convulsions, meningism, paralysis.

Eye disorders

Rare: Visual disturbances.

Very rare: Retinopathy.

Cardiac disorders

Rare: Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders

Rare: Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of breath and fever.

Rare: Pulmonary fibrosis, Pneumocystis carinii pneumonia, shortness of breath and bronchial asthma, pleural effusion.

Gastrointestinal disorders

Very common: Stomatitis, dyspepsia, nausea, loss of appetite.

Common: Oral ulcers, diarrhoea.

Uncommon: Pharyngitis, enteritis, vomiting.

Rare: Gastrointestinal ulcers.

Very rare: Haematemesis, haematorrhea, toxic megacolon.

Hepatobiliary disorders (see section 4.4)

Very common: Elevated transaminases.

Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.

Rare: Acute hepatitis.

Very rare: Hepatic failure.

Skin and subcutaneous tissue disorders Common: Exanthema, erythema, pruritus.

Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria.

Rare: Increased pigmentation, acne, ecchymosis.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.

Musculoskeletal and connective tissue disorders Uncommon: Arthralgia, myalgia, osteoporosis.

Renal and urinary disorders

Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare: Renal failure, oliguria, anuria, electrolyte disturbances.

Reproductive system and breast disorders Uncommon: Inflammation and ulceration of the vagina.

Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge.

General disorders and administration site conditions

Rare: Allergic reactions, anaphylactic shock, allergic vasculitis, fever,

conjunctivitis, infection, sepsis, wound-healing impairment,

hypogammaglobulinaemia.

Very rare: Local damage (formation of sterile abscess, lipodystrophy) of injection site following intramuscular or subcutaneous administration.

The appearance and degree of severity of undesirable effects depends on the dosage level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals.

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated.

Only mild local skin reactions were observed, decreasing during therapy.

4.9 Overdose

a)    Symptoms of overdosage

Toxicity of methotrexate mainly affects the haematopoietic system.

b)    Treatment measures in the case of overdosage

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within one hour and dosing continued until the serum levels of methotrexate are below 10^-7 mol/l.

In cases of massive overdose, hydration and urinary alkalisation may be necessary to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination. Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser.

5. PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Folic acid analogues ATC code: L01BA01

Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for the treatment of Crohn's disease.

Mechanism of action

Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriasis arthritis, chronic polyarthritis and Crohn's disease, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects.

International clinical guidelines reflect the use of methotrexate as a second choice for Crohn's disease patients that are intolerant or have failed to respond to first-line immunomodulating agents as azathioprine (AZA) or 6-mercaptopurine (6-MP).

The adverse events observed in the studies performed with methotrexate for Crohn's disease at cumulative doses have not shown a different safety profile of methotrexate than the profile it is already known. Therefore, similar cautions must be taken with the use of methotrexate for the treatment of Crohn's disease as in other rheumatic and non-rheumatic indications of methotrexate (see sections 4.4 and 4.6).

5.2    Pharmacokinetic properties

Distribution

Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of low-dosed administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are possible (25 - 100 %). Maximum serum concentrations are achieved after 1 - 2 hours.

Biotransformation

Bioavailability of subcutaneous, intravenous and intramuscular injection is comparable and nearly 100 %.

Elimination

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in particular, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts.

The terminal half-life is on average 6 - 7 hours and demonstrates considerable variation (3 - 17 hours). The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution space (pleural effusion, ascites).

Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle metabolite is 7-hydroxymethotrexate. Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus. Approx.

5 - 20 % methotrexate and 1 - 5 % 7-hydroxymethotrexate are eliminated biliary. There is pronounced enterohepatic circulation.

In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to hepatic impairment is not known.

5.3 Preclinical safety data

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic. Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered not classifiable as to its carcinogenicity to humans.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium chloride

Sodium hydroxide for pH adjustment Water for injections

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf-life

2 years.

6.4    Special precautions for storage

Do not store above 25 °C. Keep the pre-filled syringes in the outer carton in order to protect from light.

6.5    Nature and contents of container

Nature of container:

A pre-filled colourless glass syringe of 1 ml capacity, filled with a clear, yellow-brown solution. It is embedded with an injection needle with a plunger stopper of rubber and plastic rods inserted on the stopper to form the syringe. Also contains alcohol pads.

Pack sizes:

The following pack sizes are available:

Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 m and 0.50 ml of solution are available in a packsize of 1 syringe with embedded SC needle. Alcohol pads included in the package.

All pack sizes are available with graduation marks.

6.6    Special precautions for disposal and other handling

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Metex 50 mg/ml. Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with ample amount of water.

For single use only.

Any unused product or waste should be disposed of in accordance with local requirements.

Instructions for subcutaneous use

The best places for the injection are:

-    upper thighs,

-    abdomen except around the navel.

1. Clean the area around the chosen injection site (e.g. by using the enclosed alcohol pad).

2.    Pull the protective plastic cap straight off.

3. Build a skin fold by gently squeezing the area at the injection site.

4. The fold must be held pinched until the syringe is removed from the skin after the injection.

5. Push the needle fully into the skin at a 90-degree angle.

6.    Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from the skin at the same 90-degree angle.

7.    MARKETING AUTHORISATION HOLDER

Procured from the EU by Product Licence holder: Star Pharmaceuticals Ltd., 5 Sandridge Close, Harrow, Middlesex HA1 1XD. Repackaged by Servipharm Ltd.

8.    MARKETING AUTHORISATION NUMBER

PL 20636/2529

9.    DATE OF REVISION OF THE TEXT 25.04.14[S-5]

PATIENT INFORMATION LEAFLET    2529

25.04.14[5]

Methotrexate 50 mg/ml solution for injection

(methotrexate)

Read all of this leaflet carefully before you start using this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, please ask your doctor or pharmacist.

•    This medicine has been prescribed for you. 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.

This medicine is available using the above name but will be referred to as Methotrexate 50 mg/ml throughout the leaflet

In this leaflet:

1.    What Methotrexate 50 mg/ml is and what it is used for

2.    What you need to know before you use Methotrexate 50 mg/ml

3.    How to use Methotrexate 50 mg/ml

4.    Possible side effects

5.    How to store Methotrexate 50 mg/ml

6.    Contents of the pack and other information

1.    WHAT METHOTREXATE 50 MG/ML IS AND WHAT IT IS USED FOR

Methotrexate 50 mg/ml is indicated for the treatment of

•    active rheumatoid arthritis in adult patients.

•    polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.

•    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.

•    mild to moderate Crohn's Disease in adult patients when adequate treatment with other medicines is not possible.

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.

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

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

Methotrexate 50 mg/ml modifies and slows down the progression of the disease.

Crohn's Disease is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract causing symptoms such as abdominal pain, diarrhoea, vomiting or weight loss.

2.    WHAT YOU NEED TO KNOW BEFORE YOU USE METHOTREXATE 50 MG/ML

Do not use Methotrexate 50 mg/ml 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, e.g. tuberculosis, HIV or other immunodeficiency syndromes.

•    suffer from 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 Methotrexate 50 mg/ml if:

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

•    you have problems with the way your liver works.

•    you suffer from dehydration (water loss).

Recommended follow-up examinations and safety measures:

Even when Methotrexate 50 mg/ml 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 alterations of the mucosa

•    Blood tests

•    Check if your liver is working properly

•    Check if your kidneys are working properly

•    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 (e.g. herpes zoster [shingles], tuberculosis, hepatitis B or C) may flare up. During therapy with Methotrexate 50 mg/ml 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 therapy must then be stopped.

Diarrhoea can be a toxic effect of Methotrexate 50 mg/ml and requires an interruption of therapy. If you suffer from diarrhoea please speak to your doctor.

Other medicines and Methotrexate 50 mg/ml

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The effect of the treatment may be affected if Methotrexate 50 mg/ml is administered at the same time as certain other drugs:

•    Medicines harming the liver or the blood count, e.g. leflunomide

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

•    Non-steroidal anti-inflammatory drugs or salicylates (medicines against pain and/or inflammation)

•    Probenecid (medicine against gout)

•    Weak organic acids like loop diuretics (“water tablets”) or some medicines used for treatment of pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and ibuprofen) and pyrazole (e.g. metamizol for treating pain)

•    Medicinal products, which may have adverse effects on the bone marrow, e.g. trimethoprim-sulphamethoxazole (an antibiotic) and pyrimethamine

•    Sulphasalazine (antirheumatic medicine)

•    Azathioprine (an immunosuppressive agent sometimes used in severe forms of rheumatoid arthritis)

•    Mercaptopurine (a cytostatic agent)

•    Retinoids (medicine against psoriasis and other dermatological diseases)

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

•    Proton-pump inhibitors (medicines against stomach trouble)

•    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 should be avoided.

Methotrexate 50 mg/ml 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 50 mg/ml.

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.

You must not take Methotrexate 50 mg/ml during pregnancy. Men and women should use an effective method of birth control during treatment and during a further six months after treatment with Methotrexate 50 mg/ml has been discontinued.

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. 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, and men should seek advice about the possibility of sperm preservation before starting therapy.

Breast-feeding should be stopped prior to and during treatment with Methotrexate 50 mg/ml.

Driving and using machines

Treatment with Methotrexate 50 mg/ml may cause adverse reactions affecting the central nervous system, e.g. 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 you should not drive or use machines.

Important information about some of the ingredients of Methotrexate 50 mg/ml

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

3.    HOW TO USE METHOTREXATE 50 MG/ML

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

Methotrexate 50 mg/ml is administered 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. Methotrexate 50 mg/ml may be injected intramuscularly (in a muscle), intravenously (in a vein) or subcutaneously (under the skin).

As there is very little data about giving the medicine intravenously in children and adolescents, it must only be injected under the skin or into a muscle.

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

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

Method and duration of administration Methotrexate 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 Methotrexate is a long-term treatment.

At the start of your therapy, Methotrexate may be injected by medical staff.

In certain cases your doctor may decide to instruct you how to inject Methotrexate under the skin yourself. You will then receive appropriate training.

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

Please refer to the instructions for use at the end of the leaflet.

The manner of handling and disposal must be consistent with that of other cytostatic preparations in accordance with local requirements. Pregnant health care personnel should not handle and/or administer Methotrexate 50 mg/ml.

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 have the impression that the effect of Methotrexate 50 mg/ml is too strong or too weak, you should 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 require urgent specific treatment:

• persistent dry, non-productive cough, shortness of breath and fever; these may be signs of an inflammation of the lungs (pneumonia) [common — may affect up to 1 in 10 people]

*    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 of the liver (liver fibrosis), fatty degeneration of the liver [all uncommon — may affect up to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare - may affect up to 1 in 1,000 people] and liver failure [very rare - may affect up to 1 in

10,000 people]

*    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 - may affect up to 1 in 1,000 people]

*    symptoms of kidney damage such as swelling of the hands, ankles or feet or changes in frequency of urination or decrease or absence of urine; these may be signs of kidney failure [rare - may affect up to 1 in 1,000 people]

*    symptoms of infections, e.g. fever, chills, achiness, sore throat;

methotrexate can make you more susceptible to infections. Rarely [may affect up to 1 in 1,000 people] severe infections like a certain type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis) may occur

*    severe diarrhoea, vomiting blood and black or tarry stools; these symptoms may indicate a rare [may affect up to 1 in 1,000 people] severe complication of the gastrointestinal system caused by methotrexate e.g. gastrointestinal ulcers

*    fever and serious deterioration of your general condition, or sudden fever accompanied by a sore throat or mouth, or urinary problems; methotrexate can very rarely [may affect up to 1 in 10,000 people] cause a sharp fall in white blood cells (agranulocytosis) and severe bone marrow suppression

*    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 - may affect up to 1 in 10,000 people]

*    severe skin rash or blistering of the skin (this can also affect your mouth, eyes and genitals); these may be signs of the very rare [may affect up to 1 in 10,000 people] conditions called Stevens Johnson syndrome or burned skin syndrome (toxic epidermal necrolysis)

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

Very common: may affect more than 1 in 10 people

*    Mouth inflammation, indigestion, nausea (feeling sick), loss of appetite

*    Increase in liver enzymes

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 (leukopenia, anaemia, thrombocytopenia)

Uncommon: may affect up to 1 in 100 people

*    Throat inflammation, inflammation of the bowels, vomiting

*    Increased sensitivity to light, loss of hair, increased number of rheumatic nodules, shingles, inflammation of blood vessels, herpeslike skin rash, hives

*    Onset of diabetes mellitus

*    Dizziness, confusion, depression

*    Decrease in serum albumin

*    Decrease in the number of blood cells and platelets

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

*    Joint pain, muscle pain, osteoporosis (reduction of bone mass)

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

*    Increased skin pigmentation, acne, blue spots due to vessel bleeding

*    Allergic inflammation of blood vessels, fever, red eyes, infection, wound-healing impairment, decreased number of anti-bodies in the blood

*    Visual disturbances

*    Inflammation of the sac around the heart, accumulation of fluid in the sac around the heart

*    Low blood pressure, occlusion of a blood vessel by dislodged blood clot (thromboembolic events)

*    Lung fibrosis, shortness of breath and bronchial asthma, accumulation of fluid in the sac around the lung

*    Electrolyte disturbances

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

*    Profuse bleeding, toxic megacolon (acute toxic dilatation of the gut)

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

*    Local damage (formation of sterile abscess, changes in the fatty tissue) of injection site following administration into a muscle or under the skin

*    Impaired vision, pain, loss of strength or sensation of numbness or tingling in arms and legs, changes in taste (metallic taste), convulsions, paralysis, severe headache with fever

*    Retinopathy (noninflammatory eye disorder)

*    Loss of sexual drive, impotence, male breast enlargement (gynaecomastia), defective sperm formation, menstrual disorder,

*    vaginal discharge

*    Enlargement of lymphatic nodes (lymphoma)

When methotrexate is given by the intramuscular route, local undesirable effects (burning sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of injection can occur commonly. Subcutaneous application of methotrexate is locally well tolerated.

Only mild local skin reactions were observed, decreasing during therapy.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Methotrexate 50 mg/ml

Keep out of the sight and reach of children.

Do not store above 25 °C.

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

Do not use after the expiry date stated on the packaging. The expiry date refers to the last day of that month.

Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required.

The measures will help to protect the environment

6. Further information

What Methotrexate 50 mg/ml contains

*    The active substance is methotrexate.

1 ml of solution contains 50 mg methotrexate as (methotrexate disodium).