Document: leaflet MAH GENERIC_PL 01502-0076 change

• leaflet MAH GENERIC_PL 01502-0076
• leaflet MAH GENERIC_PL 11587-0050

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Patient Information Leaflet

Methotrexate 2.5 mg/ml solution for injection

methotrexate

Read all of this leaflet carefully before this medicine is administered to you because it contains important information for you.

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

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

•    This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

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

1.    What Methotrexate 2.5 mg/ml solution for injection is and what it is used for

Methotrexate is one of a group of medicines known as antimetabolites. It is used in the treatment of cancer as well as psoriasis including psoriatic arthritis. It stops a substance called dihydrofolate reductase from working. This substance is an enzyme, which is important in “cell growth (replication)”. By inhibiting the enzyme, cancer cells will eventually “die”.

Methotrexate helps patients with psoriasis by killing the cells in the skin that are growing too fast. It is these rapidly growing cells that cause the raised patches of skin in psoriasis.

2.    What you need to know before receiving Methotrexate 2.5 mg/ml solution for injection

Do NOT use    Methotrexate

2.5 mg/ml solution for injection

•    if you have ever had any allergic reaction to

methotrexate or any of the ingredients of this product

•    if you have severe problems with your kidneys

•    if you have severe problems with your liver, including alcoholic liver disease, abnormal blood counts, fibrosis, cirrhosis or recent active hepatitis

•    if you suffer from alcoholism

•    if you have any serious blood disorders (anaemia, a reduction in white cell number (leucopenia) or platelet number (thrombocytopenia))

•    if you have an active infection

•    if you have a medical condition or are receiving medication, which lowers your resistance to infection

•    if you are pregnant or intend to become pregnant, or are breast-feeding, as the drug can harm unborn and breast-fed infants.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Methotrexate 2.5 mg/ml solution for injection

•    if you have impaired respiratory function

•    if you have mild to moderate kidney or liver problems, or a mild to moderate blood disorder;

•    if you have diarrhoea

•    if you have ulcers in your mouth, stomach or intestine (large bowel)

•    if you have ascites (collection of liquid in the free abdominal cavity) and/or pleural effusions (collection of liquid in the pleural cavity)

•    if you are receiving or intend to receive any vaccine, as methotrexate can reduce their effect

•    if you have had radio- or chemotherapy before (especially of the pelvis), or are receiving radiotherapy concurrently

•    if you have an impaired general condition (if you feel weak or infirm)

•    if you are of advanced age

•    if Methotrexate 2.5 mg/ml solution for injection is given to very young children.

This medicinal product contains 0.16 mmol (or 3.7 mg) sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Please consult your doctor, even if these statements were applicable to you at any time in the past.

Other medicines and Methotrexate 2.5 mg/ml solution for injection

Tell your doctor, pharmacist or nurse if you are taking,have recently taken,or might take any other medicines, including medicines obtained without a prescription.

Medications which can be influenced by or can influence the effect of methotrexate negatively

•    pain-killers such as salicylates (e.g. aspirin), amidopyrine derivatives, phenylbutazone and leflunomide

•    diphenylhydantoins (e.g. phenytoin, an antiepileptic agent)

•    barbiturates and tranquillisers (sedative agents)

•    antibiotics (medication against bacteria), e.g. tetracyclines, penicillins, chloramphenicol, cotrimoxazole and sulphonamides

•    cytostatics (medication against cancer), e.g. cytarabine, doxorubicin, mercaptopurine, procarbazine, cisplatin, L-asparaginase and 5-fluorouracil

•    Disease-modifying antirheumatic drugs (DMARD;

•    pyrimethamine (medication against malaria)

•    cholestyramine (lipid-lowering agent)

•    acitretin or other retinoids (for psoriasis or skin disorders)

•    theophylline (used mainly in bronchial asthma)

•    erythrocyte concentrates (for blood transfusion)

•    nitrous oxide-based anaesthetics

•    Proton pump inhibitors (used in the therapy of gastric ulcers) e.g. omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole

•    sulphasalazine (for ulcerative colitis)

•    tetrahydrofolic acid preparations

•    oral antidiabetics (medications to treat diabetes) and diuretics (increase urine output)

•    hypoglycaemics (lower blood sugar levels)

•    other medicinal products with nephrotoxic and hepatotoxic potential (incl. alcohol)

•    vaccinations

•    azathioprine (an immunosuppressive drug)

•    vitamin preparations containing folic acid or its derivates

Please note that these statements may also apply to products used some time ago or at some time in the future.

Pregnancy and breast-feeding

Do not take Methotrexate 2.5 mg/ml solution for injection if you are pregnant because it causes a variety of malformations or even the death of the foetus.

Women must not get pregnant during treatment with Methotrexate 2.5 mg/ml solution for injection. If you get pregnant during treatment with Methotrexate

2.5    mg/ml solution for injection, please inform your doctor immediately!

Special indications for contraception Methotrexate temporarily influences sperm and egg production. During treatment and up to 6 months after treatment is stopped, you must practice effective contraception. In this respect, it is of no importance whether the male or the female partner takes Methotrexate 2.5 mg/ml solution for injection!

Do not take Methotrexate 2.5 mg/ml solution for injection during breast-feeding, since methotrexate is excreted into the breast milk. Methotrexate can seriously harm breast-fed infants.

3.    How Methotrexate 2.5 mg/ml solution for injection is administered

Dosage

Your doctor will decide on a suitable dose for you. Doses vary considerably and will depend on the underlying disease.

Your doctor may instruct you to take sodium bicarbonate or acetazolamide tablets while receiving your injections to help make sure that methotrexate is not concentrated in the kidneys. If you receive methotrexate in high doses, you will receive calcium folinate as well to lessen the side effects of methotrexate.

It is possible that you will only get methotrexate. In the case of cancer, it is also possible that you will receive so-called combination therapy in which you must take several medications.

Your body weight, age, general condition of health, your response to the drug and whether other medicines are required at the same time will also influence the dose you receive.

Method of Administration

Your doctor or nurse will give you Methotrexate

2.5    mg/ml solution for injection injecting it either into the central nervous system (intraventricular or intrathecal administration), into one of your veins (e.g. as bolus or infusion), arteries, or a muscle.

Tests during treatment with Methotrexate

During your treatment, you will have a number of tests, such as regular blood tests to check that appropriate blood levels of methotrexate are attained and that your kidneys are eliminating excess drug properly.

Other tests are performed routinely at the start and during the course of therapy (e.g. chest X-ray, liver function test, full blood count and urinalysis).

4.    Possible Side Effects

Like all medicines Methotrexate 2.5 mg/ml solution for injection can cause side effects although not everybody gets them.

The frequency of side effects is classified into the following categories:

Very common	in more than 1 in 10 patients
Common	in more than 1 in 100 patients, but less than 1 in 10 patients
Uncommon	in more than 1 in 1,000 patients, but less than 1 in 100 patients
Rare	in more than 1 in 10,000 patients, but less than 1 in 1,000 patients
Very rare	in less than 1 in 10,000 patients, including isolated reports
Not known	cannot be estimated from the available data

Methotrexate has the potential for serious, sometimes fatal toxicity. Because the toxic reactions can occur at any time during therapy, your doctor should observe you closely and must inform you of early signs and symptoms of toxicity.

If you think you have an infection, a sore throat, fever or chills during treatment, you should tell your doctor immediately.

The most common undesirable effects are ulcerative stomatitis, leucopenia, nausea, and abdominal discomfort.

Undesirable effects of Methotrexate 2.5 mg/ml solution for injection are

Neoplasms

Uncommon: Lymphoma

Very rare: Tumour lysis syndrome (renal failure due to massive destruction of rapidly growing tumour cells)

Blood disorders

Common: Blood picture changes - e.g. your vulnerability for infections may increase, you may suffer from unusual bleeding or bruising and you may observe signs of anaemia (weakness, tiredness, difficulties in breathing) Immune system disorder

Uncommon: Allergic reactions, decreased resistance to infection Metabolism and endocrine disorders Uncommon: Diabetes

Rare:    Hyperuricaemia (increased blood

levels of uric acid, possibly leading to gout)

Psychiatric disorders Rare:    Mood swings, irritability

Nervous system disorders Common: Headache, drowsiness, sleepiness Uncommon: Seizures, leucoencephalopathy (inflammation of the brain), manifested by ventricular enlargement (expansion of the fluid spaces inside the brain), incomplete palsy affecting one or both sides of the body, confusion, dizziness

Rare:    Speech disorder, subtle cognitive

dysfunction (easily    disturbed

attention), mental disturbance Very Rare: Unusual sensations in the head, pain, paraesthesia (pins-and-needles sensation), muscle weakness, significant    intellectual deficit,

dementia, cerebral oedema (swelling of the brain) after administration into the central nervous system possibly leading to vomiting, fits, coma and even death Eye disorders

Rare:    Impairment of vision

Very rare: Swelling, inflammation of the eyelid edges, conjunctivitis (inflammation of the eye conjunctiva), unusual formation of tears, photophobia Ear disorders

Rare:    Ringing in the ears

Cardiac disorders

Rare:    Low blood pressure, pericarditis

(inflammation of the outer lining of the heart), pericardial effusion and tamponing (collection of fluid and blood, respectively, in the space between the outer lining of the heart and the heart muscle)

Vascular disorders

Uncommon: Vasculitis (inflammation of blood vessels)

Rare:    Haematoma, point-like or small flat

bleeding, complications resulting from the formation of blood clots in veins and arteries Lung disorders

Common:    Inflammation and fibrosis (increase in

the connective tissue); the pulmonary toxicity may manifest as fever, cough (especially dry and nonproductive), difficulties or increase in the frequency of breathing, chest pain, hypoxaemia (lack of oxygen in the blood), and/or abnormal findings on chest radiography and/or tests of respiratory function

Rare:    Upper respiratory tract infection

Gastro-intestinal disorders

Very

common:    Disorders of the mouth, stomach

and intestines like mucositis (mucus membrane inflammation, e.g. inflammation of the gums, tongue, throat, mouth, intestines), lack of appetite, feeling sick Common:    Diarrhoea

Uncommon: Vomiting, gastrointestinal ulcerations, inflammation of the pancreas Rare:    Malabsorption (disturbances of

uptake of nutrition with consequences such as body weight loss), melaena (red to black stools)

Very rare:    Unusual bleeding from the mouth,

stomach and intestines, increased risk of perforation and toxic megacolon (severe complication with massive dilatation of the colon and severe pain

Liver and gall bladder disorders Uncommon: Fibrosis (increase in the connective tissue), cirrhosis (transformation of the tissue with hardening and abolition of the normal structure of the organ), fatty degeneration of the liver or other histologic (tissue) changes in the liver

Rare:    Hepatitis (inflammation of the liver)

Very rare:    Acute liver cell death

Skin disorders

Common: Rash, itching, formation of blisters, redness and inflammation Uncommon: Loss of hair, nettle rash, photosensitivity, pigmentary changes (discolouration of the skin), loss of skin tissue

Rare:    Acne, an increase in rheumatic

nodules, increased colouration or inflammation or detachment of the nails, nodulosis (formation of nodules under the skin)

Very rare: Telangiectasia (expansion of small superficial blood vessels in the skin), worsening of psoriasis (with concomitant UV therapy), formation of boils, a ..recall" of radiation dermatitis (inflammation of the skin) and sunburn Musculoskeletal disorders

Uncommon: Osteoporosis, pain in the joints, muscle pain

Very rare: Aseptic necrosis of the femoral head (loss of bone tissue in the hip joint) Renal and urinary disorders Common: Impairment of renal function Uncommon: Renal failure, inflammation of the urinary bladder, pain or difficulty in passing urine

Very rare: Blood in the urine Pregnancy and lactation Uncommon: Malformations of the foetus Rare:    Abortion

Reproductive and breast disorders Uncommon: Vaginal discomfort Rare:    Menstrual dysfunction (periods may

become less frequent or even stop completely)

Very rare: Reduced or faulty formation of sperm and egg cells, infertility, loss of interest in sex / impotence, development of the breast gland in males General disorders

Uncommon: Fever without any detectable cause Rare:    Chills, malaise and undue fatigue,

sweating

Very rare: Sudden death In cases of acute lymphocytic leukaemia, methotrexate can cause pain in the left epigastric region (the area overlying the stomach, below the left lower border of the rib cage; inflammation of the space above the spleen due to destruction of the leukaemic cells).

Other possible complications from administration into the central nervous system include Guillain-Barre syndrome (inflammation of the central nervous system), nerve palsies, and cerebellar dysfunction like ataxia (disturbance of balance and coordination), arachnoiditis (inflammation of one of the membranes surrounding the spinal cord) manifested as headache, back pain, neck stiffness, and/or fever, subacute myelopathy (disorder affecting the spinal cord) manifested as complete or incomplete palsy of the lower limbs (paraparesis or paraplegia).

There have been reports on the manifestation of lymphomas which were, in some cases, reversible after discontinuing methotrexate therapy. The potential of methotrexate to produce other cancers in humans has been evaluated in several studies, but the results do not confirm a cancerogenic risk.

5. How to store Methotrexate 2.5 mg/ml solution for injection

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

•    Keep the vial in the outer carton in order to protect from light.

•    Do not store above 25°C.

•    For single dose use only. Discard any unused solution immediately and safely after initial use.

•    This medicine should only be administered by a medically qualified person, e.g. a doctor.

•    Methotrexate 2.5 mg/ml solution for injection should not be used after the expiry date printed on the label.

•    Any unused product or waste should be disposed of in accordance with local requirements for example by incineration.

6. Contents of the pack and other information

What Methotrexate 2.5 mg/ml solution for injection contains

The active substance is methotrexate.

Each 1 ml of this sterile solution for injection contains 2.5 milligrams methotrexate.

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

What Methotrexate 2.5 mg/ml solution for injection looks like and contents of the pack Methotrexate 2.5 mg/ml solution for injection is a yellowish and sterile solution in clear glass vials. The solution for injection is available in packs of 1, 5 or 10 vials containing 2 ml solution.

Not all pack sizes may be marketed.

Marketing Authorisation Holder hameln pharmaceuticals ltd Gloucester, United Kingdom Manufacturer

Haupt Pharma Wolfratshausen GmbH Pfaffenrieder Str. 5, 82515 Wolfratshausen, Germany

This leaflet was last approved in December 2014

2005_031_03 PB Methotrexate 2.5mgml.indd 10/01/2014