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PACKAGE LEAFLET: INFORMATION FOR THE USER

Methotrexate 25 mg/ml solution for injection, pre-filled syringe

Methotrexate

In this leaflet:

1.    What Methotrexate is and what it is used for

2.    What you need to know before you use Methotrexate

3.    How to use Methotrexate

4.    Possible side effects

5.    How to store Methotrexate

6.    Contents of the pack and other information

1.    WHAT METHOTREXATE IS AND WHAT IT IS USED FOR

Methotrexate is a drug with the following properties:

-    it interferes with the growth of certain cells in the body that reproduce quickly (anti-tumour agent),

-    it reduces undesired reactions of the body’s own defence mechanism (immunosuppressant), and

-    it has anti-inflammatory effects.

Methotrexate is used for the treatment of:

-    active rheumatoid arthritis (RA) in adult patients where treatment with disease modifying antirheumatic drugs (DMARDs) is indicated.

-    polyarthritic forms (when five or more joints are involved) of severe, active juvenile idiopathic arthritis (JIA) when the response to so-called non-steroidal anti-inflammatory drugs (NSAIDs) has been inadequate

-    severe forms of psoriasis, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriasis affecting the joints (psoriatic arthritis).

2.    WHAT YOU NEED TO KNOW BEFORE YOU USE METHOTREXATE

Important warning with reference to the dosing of methotrexate:

Methotrexate for the therapy of rheumatic diseases or diseases of the skin must only be used once weekly. Incorrect dosing of methotrexate may lead to serious adverse effects including a fatal outcome. Please read section 3 of this Leaflet very carefully.

Please ask your doctor or pharmacist before using Methotrexate if you have any questions.

Do not use Methotrexate

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

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

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

-    if you have disorders of the blood-forming system.

-    if you have increased alcohol consumption.

-    if you have an impaired immune system.

-    if you have severe or existing infections, e.g. tuberculosis and HIV.

-    if you have gastrointestinal ulcers.

- if you are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and male fertility”).

You should not be given live vaccines during treatment with Methotrexate.

Warning and precautions

Talk to your doctor or pharmacist before using Methotrexate

-    if you have diabetes mellitus treated with insulin.

-    if you have inactive, prolonged infections (e.g. tuberculosis, hepatitis B or C, shingles [herpes zoster]).

-    if you have or have had any liver or kidney disease.

-    if you have problems with your lung function.

-    if you are severely overweight.

-    if you have abnormal accumulation of liquid in the abdomen, in the cavity between the lungs and chest wall (ascites, pleural effusions).

-    if you are dehydrated or suffer from conditions leading to dehydration (vomiting, diarrhoea, stomatitis).

The therapy is to be administered once a week.

Incorrect intake of methotrexate can lead to severe, including potentially lethal, side effects.

Read section 3 of this package leaflet carefully.

If you experienced problems with your skin after radiation therapy (radiation induced dermatitis) and sun-burn, these conditions can reappear under methotrexate therapy (recall-reaction).

Children, adolescents and elderly

Dosage instructions for children and adolescents with polyarthritic forms of juvenile idiopathic arthritis depend on patients body surface area.

Use in children below 3 years of age is not recommended due to the insufficient experience in this age group.

Children and the elderly should be kept under particularly close medical surveillance during treatment with Methotrexate, in order to identify possible side effects as early as possible. Dosage for elderly patients should be relatively low due to age-related reduced liver and kidney function and low folate reserves.

Special precautionary measures during treatment with Methotrexate:

Methotrexate should only be prescribed by doctors with sufficient experience in the Methotrexate treatment of the disease concerned.

Methotrexate temporarily affects sperm and egg production. You and your partner must avoid conception (becoming pregnant or fathering children) if currently receiving methotrexate and for at least six months after your treatment with methotrexate has stopped (see also section “Pregnancy, breast-feeding and male fertility”).

Skin changes caused by psoriasis can worsen during treatment with Methotrexate if exposure to UV irradiation occurs at the same time.

Recommended follow up examinations and precautions:

Even if Methotrexate is administered at low doses, severe side effects can occur. In order to diagnose them early, regular monitoring by the doctor at short-term intervals is necessary. Before treatment is started your doctor may carry out blood tests, and also check how well your kidneys and liver are working. You may also have a chest X-ray. Further tests may also be done during and after treatment. Do not miss appointments for blood tests.

If the results of any of these tests are abnormal, treatment will only be resumed when all readings are back to normal.

Other medicines and Methotrexate

Please tell your doctor or pharmacist if you are taking, have recently taken or want to start taking any other medicines, including medicines obtained without a prescription and herbal or natural medicinal products.

Remember to tell your doctor about your treatment with Methotrexate, if you are prescribed another medicine while the treatment is still ongoing.

It is especially important to tell your doctor if you are using:

-    other treatments for rheumatoid arthritis or psoriasis such as leflunomide, sulfasalazine (also used for ulcerative colitis), acetylsalicylic acid, phenylbutazone, or amidopyrine

-    alcohol (should be avoided)

-    live vaccinations

-    azathioprine (used to prevent rejection after an organ transplantation)

-    retinoids (used to treat psoriasis and other skin disorders)

-    anticonvulsant drugs (used to prevent fits)

-    cancer treatments

-    barbiturates (sleeping injection)

-    tranquillisers

-    oral contraceptives

-    probenecid (used to treat gout)

-    antibiotics

-    pyrimethamine (used to prevent and treat malaria)

-    vitamin preparations, which contain folic acid

-    proton-pump inhibitors (used to treat severe heartburn or ulcers)

-    theophylline (used to treat asthma)

Methotrexate with food, drink and alcohol

During treatment with this medicine you should avoid any alcohol consumption as well as excessive consumption of coffee, caffeine-containing beverages, or black tea. Also make sure you drink plenty of liquids during treatment with Methotrexate because dehydration (reduction in body water) can increase the toxicity of Methotrexate.

Pregnancy, breast-feeding and male fertility

Pregnancy

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

If you do become pregnant during treatment, you should be offered advice regarding the risk of harmful effects on the child through treatment. If you wish to become pregnant you should consult your doctor, who may refer you for specialist advice, before the planned start of treatment, because methotrexate may be genotoxic, which means that the medicine may harm your unborn baby.

Breast-feeding

Do not breast-feed during treatment, because methotrexate passes into breast milk. If your attending doctor considers treatment with methotrexate as absolutely necessary during the lactation period, you must stop breast-feeding (see also section “Do not use Methotrexate”).

Male fertility

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

Driving and using machines

Tiredness and dizziness can occur during treatment. If affected, you should not drive or operate machinery.

Important information about some of the ingredients of Methotrexate

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially ‘sodium-free’.

3. HOW TO USE METHOTREXATE

This medicine should only be prescribed by physicians, who are familiar with the various characteristics of the medicinal product and its mode of action.

Always use Methotrexate exactly as your doctor has told you. You should check with your doctor or pharmacist if you are unsure.

Methotrexate is administered once a week only. Together with your doctor you should decide on a suitable fixed weekday each week on which you receive your injection.

Incorrect intake of Methotrexate can lead to severe, including potentially lethal, side effects.

The recommended dosage is:

Dosage in patients with rheumatoid arthritis The recommended starting dose for methotrexate is 7.5 mg once a week. Methotrexate is given in a single application as injection under the skin or into a muscle (see section “Method and duration of administration”).

In case of inadequate action and if tolerated well, Methotrexate doses may be gradually increased by 2.5 mg per week. The mean weekly dose is 15-20 mg. Generally, a weekly dose of 25 mg Methotrexate should not be exceeded. Upon achieving the desired therapeutic results, the dose should be reduced gradually to the lowest possible effective maintenance dose. Use in children and adolescents

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

The recommended dose is 10-15 mg/m² body surface area per week. In cases with inadequate response, the weekly dosage may be increased up to 20 mg/m2 body surface area/week. However, regular check-ups should be done more often.

Use in children below 3 years of age is not recommended due to the insufficient experience in this age group.

Dosage in adult patients with psoriasis or psoriatic arthritis Recommended initial dose (for an average body weight of 70 kg):

It is recommended to administer a single test dose of 5-10 mg, in order to assess possibly damaging effects.

This dose can be administered subcutaneously (under the skin) or intramuscularly (into a muscle).

If, one week later, no blood count changes are observed, therapy is continued with a dose of approximately 7.5 mg. The dose may be gradually increased (in steps of 5-7.5 mg per week and under blood count surveillance) until ideal therapeutic results are obtained. Generally, a weekly dose of 25 mg should not be exceeded. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression.

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 Upon achieving the desired therapeutic results, the dose should be weekly reduced to the lowest possible effective maintenance dose for the individual patient.

Patients with kidney disorders

Patients with a kidney disorder may need a reduced dose.

Method and duration of administration

For subcutaneous and intramuscular use.

Any unused solution should be discarded (see also section “How to store Methotrexate”).

The duration of treatment is determined by the treating physician. Methotrexate is injected once weekly! It is recommended to specify a certain day of the week as “day for injection”.

Methotrexate is given as injection under the skin or into a muscle.

Treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris and psoriatic arthritis with Methotrexate is a long-term treatment.

Rheumatoid arthritis

Generally, improvement of the symptoms can be expected after 4-8 weeks of treatment. Symptoms may return after Methotrexate treatment is stopped.

Severe types of psoriasis vulgaris and psoriatic arthritis (psoriasis arthropathica)

Generally, response to treatment can be expected after 26 weeks. Depending on symptoms severity and on laboratory parameters, the therapy is then continued or discontinued.

At the start of your therapy, Methotrexate may be injected by a doctor. However, your doctor may decide that it is right for you to learn how to inject Methotrexate yourself. You will receive appropriate training for you to do this. Under no circumstances should you attempt to inject yourself unless you have been trained to do so.

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The following information is intended for medical or healthcare professionals only: PREPARATION GUIDE FOR:

Methotrexate 25 mg/ml solution for injection, pre-filled syringe

Pre-filled syringe

Methotrexate for the therapy of rheumatic or skin diseases must only be used once weekly.

Please refer to Summary of Product Characteristics for full prescribing and other information.

Instructions for use and handling and disposal

The solution is to be visually inspected prior to use. Only clear solutions practically free from particles should be used. Handling and disposal must be consistent with that of other cytotoxic preparations in accordance with local requirements. Pregnant health care professionals should not handle and/or administer Methotrexate.

If you use more Methotrexate than you should

Do not change the dosage by yourself!

Use Methotrexate according to the doctor’s orders or according to the dosage directions stated in this package leaflet. If you use more of this medicine than you should, a physician or nearest hospital casualty department must be contacted immediately.

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

Take your medicine package with you if you go to a doctor or hospital. The antidote in case of an overdose is calcium folinate.

If you forget to use Methotrexate

Do not take a double dose to make up for forgotten individual doses, but continue taking the ordered dose. Ask your doctor for advice.

If you stop taking Methotrexate

You should not interrupt or discontinue your treatment with Methotrexate, unless you have discussed this with your doctor. If you suspect severe side effects, contact your doctor immediately for advice.

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

Step-by-step instructions for subcutaneous injection:

Setting up for an injection:

•    Open the box on a flat surface. Read the package leaflet carefully.

•    Take one pre-filled syringe out of the box without shaking it.

•    Visually inspect the solution in the syringe.

•    Choose an injection site. Wipe the injection site with an alcohol pad, using a circular motion. Do not touch this area before injection. You will be instructed in detail by your doctor.

Injecting the solution:

•    Remove the needle cover by firmly pulling it straight off the syringe. Be careful not to bend or twist the cover during removal to avoid damage to the needle.

•    When you remove the needle cover, there may be a drop of liquid at the end of the needle. This is normal. Do not touch the needle or allow it to touch any surface. Do not touch or bump the plunger to avoid loss of fluid.

•    With two fingers, form a skin fold and puncture it almost vertically. With a quick, short motion, push the needle completely into the skin fold. There is no need to aspirate prior to injection.

•    Push the plunger down and inject the fluid at a slow, steady rate.

End of injection:

• Remove the needle. Be careful to keep it at the same angle as inserted.

•    Dab the injection site with a swab. Do not rub as this will cause irritation at the injection site.

•    To avoid any injuries, carefully put the needle cover back on the needle by gently pressing it into place.

4. POSSIBLE SIDE EFFECTS

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

Tell your doctor straight away if you get any sudden wheeziness; difficulty in breathing; swelling of the eyelids, face or lips; rash or itching (especially affecting your whole body).

Serious side effects

If you develop any of the following side effects, contact your doctor immediately:

-    lung complaints (symptoms may be general illness; dry, irritating cough; shortness of breath, breathlessness at rest, chest pain, or fever)

-    severe peeling or blistering of the skin

-    unusual bleeding (including vomiting blood) or bruising

-    severe diarrhoea

-    ulcers in mouth

-    blistering of mucous membranes

-    black or tarry stools

-    blood in the urine or stools

-    tiny red spots on the skin

-    fever

-    yellowing of the skin (jaundice)

-    tenderness in the upper right area of your abdomen

-    pain or difficulty in passing urine

-    thirst and/or frequent urination

-    fits (convulsions)

-    loss of consciousness

-    blurred or decreased vision

-    brain disorder

The following side effects have also been reported:

Very common (affects more than 1 user in 10):

Inflammation of the mouth, indigestion, loss of appetite, nausea (feeling sick), vomiting, tummy pain, inflammation and ulcers in the mouth and throat, and increase in liver enzymes (can be detected by a test carried out by a doctor).

Common (affects 1 to 10 users in 100):

Changes in the number of blood cells and platelets (can be detected by a test carried out by a doctor), inflammation of the lungs (pneumonia) with dry, non productive cough, shortness of breath and fever, headache, tiredness, sleepiness, diarrhoea, measles-like rash (alone), redness, and itching. Uncommon (affects 1 to 10 users in 1,000):

Spinning sensation, confusion, depression, fits, inflammation of blood vessels, lung damage, ulcers and bleeding in the digestive tract, liver disorders (can be detected by a test carried out by a doctor), diabetes, decreased blood protein (can be detected by a test carried out by a doctor), nettle rash (alone), light sensitivity, brown skin, hair loss, increase of rheumatic nodules (lumps of tissues), shingles, painful psoriasis, joint or muscle pain, brittle bones, inflammation and ulcers in the bladder (possibly with blood in the urine), painful urination, severe allergic reactions, inflammation and ulcers of the vagina, slow wound healing.

Rare (affects 1 to 10 users in 10,000):

Inflammation of the lining of the heart, fluid around the heart, severely visual disturbance, mood alterations, low blood pressure, blood clots, sore throat, interruption of breathing, asthma, inflammation of the digestive tract, bloody stools, inflamed gums, abnormal digestion, acute hepatitis (inflammation of the liver), changed colour of nails, acne, red or purple spots, bone fracture, kidney failure, little or no urine production, waste products in the blood, decreased number of red blood cells, electrolyte disturbances, defective sperm formation, menstruation disorders.

Very rare (affects less than 1 user in 10,000) and frequency not known:

Infections, liver disorders, low level of antibodies, severe failure of the bone marrow (can be detected by a test carried out by a doctor), swollen glands, sleeplessness, pain, muscle weakness, pins and needles, breathing disorders, changes in sense of taste (metallic taste), inflammation of the lining of the brain causing paralysis or vomiting, red eyes, damage to the retina of the eye, fluid on the lungs, vomiting blood, cold sores, protein in the urine (can be detected by a test carried out by a doctor), loss of sex drive, problems having an erection, infection around a fingernail, severe complication of the digestive tract, boils, small blood vessels in the skin, fungal infections, damage to the blood vessels of the skin, lumps in the armpit or groin, vaginal discharge, infertility, male breast enlargement (gynaecomastia).

Other:

After injection into a muscle, there may be a burning sensation or damage at the injection site. After injection under the skin there may be a mild skin reaction.

Methotrexate may cause a reduction in the number of white blood cells and your resistance to infection may be decreased. If you experience an infection with symptoms such as fever and serious deterioration of your general condition, or fever with local infection symptoms such as sore throat/sore pharynx/sore mouth or urinary problems you should see your doctor immediately. A blood test will be taken to check for possible reduction of white blood cells (agranulocytosis). lt is important to inform your doctor about your medicine. Methotrexate may cause serious (sometimes life-threatening) side effects. Therefore, your doctor will do tests to check for abnormalities developing in the blood (e.g. low white blood cells, low platelets, lymphoma) and changes in the kidney and the liver.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via 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

Keep out of the reach and sight of children.

Do not use Methotrexate after the expiry date which is stated on the label of the pre-filled syringe and the carton after “EXP”. The expiry date refers to the last day of that month. Keep the pre-filled syringes in the outer carton in order to protect from light.

Do not store above 25°C.

Do not refrigerate or freeze.

Do not use Methotrexate if you notice the solution is not clear and free of particles or if the container is damaged.

This medicinal product must not be mixed with other medicinal products.

The product has to be used immediately after opening.

For single use only. Any unused solution should be discarded! Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging no longer required. These measures will help to protect the environment.

6.    CONTENTS OF THE PACK AND OTHER INFORMATION

What Methotrexate contains

The active substance is methotrexate.

1 ml of solution for injection contains 25 mg methotrexate.

1 pre-filled syringe with 0.3 ml contains 7.5 mg methotrexate.

1 pre-filled syringe with 0.4 ml contains 10 mg methotrexate.

1 pre-filled syringe with 0.6 ml contains 15 mg methotrexate.

1 pre-filled syringe with 0.8 ml contains 20 mg methotrexate.

1 pre-filled syringe with 1.0 ml contains 25 mg methotrexate.

The other ingredients are: sodium chloride, sodium hydroxide (for pH adjustment) and water for injections.

What Methotrexate looks like and contents of the pack

Methotrexate is a clear, yellowish solution for injection available in pre-filled syringes with attached needle.

Each box contains 1 pre-filled syringe with (each) 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml or 1.0 ml solution for injection.

Marketing Authorisation Holder

hameln pharmaceuticals ltd

Gloucester

United Kingdom

Manufacturer

hameln rds a.s.

Horna 36, 900 01 Modra

Slovak Republic

This leaflet was last approved in 06/2015.

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The following information is intended for medical or healthcare professionals only: (Continued from overleaf)

Methotrexate 25 mg/ml solution for injection, pre-filled syringe

Any contact of methotrexate with skin and mucosa is to be avoided! In case of contamination, the affected parts are to be rinsed immediately with plenty of water!

For single use only. Any unused solution should be discarded. Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

Incompatibilities

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

Special precautions for storage

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

Do not store above 25°C.

Do not refrigerate or freeze.