Methotrexate 100mg/Ml Solution For Injection
medac GmbH 1.3.1.1.1 document page: 1
Package leaflet: Information for the patient
Methotrexate 100 mg/ml solution for injection
Methotrexate
WARNINGS
The dose must be adjusted carefully depending on the body surface area if methotrexate is used for the treatment of cancer.
Fatal cases of intoxication have been reported after administration of incorrect calculated doses. Read all of this leaflet very carefully before this medicine is administered to you. If you have any further question please ask your doctor or pharmacist for advice.
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 any further questions, ask your doctor or pharmacist.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Methotrexate 100 mg/ml is and what it is used for
2. What you need to know before receiving Methotrexate 100 mg/ml
3. How Methotrexate 100 mg/ml is administered
4. Possible side effects
5. How to store Methotrexate 100 mg/ml
6. Contents of the pack and further information
1. What Methotrexate 100 mg/ml is and what it is used for
Methotrexate is one of a group of medicines known as antimetabolites which affect cell growth, including the growth of cancer cells. It is used in the treatment of cancer and 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 is used alone or in combination with other medicines to treat certain types of cancer such as:
• leukaemia (acute lymphocytic leukaemias (ALL))
• breast cancer
• bone cancer (osteosarcoma)
• bladder cancer
• head and neck cancer
• gynaecologic cancer (choriocarcinoma, trophoblastic disease - tumour development directly associated with pregnancy)
• cancer of the lymphatic system (Non-Hodgkins lymphoma, primary central nervous system lymphoma)
2. What you need to know before receiving Methotrexate 100 mg/ml
Before you start with your treatment with this medicine, you should talk to your doctor about possible benefits and risks of your therapy.
You must not receive Methotrexate 100 mg/ml
• if you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6)
• if you have severe problems with your kidneys (renal insufficiency with creatinine clearance less than 60 ml/min)
• if you have severe problems with your liver (liver insufficiency), including alcoholic liver disease, abnormal blood tests, 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 a bone marrow suppression
• if you have a severe active infection (symptoms e.g. fever, chills)
• if you have a medical condition or are receiving medicines, which lower your resistance to
infection
• if you are pregnant or intend to become pregnant you and your partner should avoid conception (becoming pregnant or fathering children) for at least six months after your treatment with methotrexate has stopped (see section 2: Pregnancy, breast-feeding and fertility)
• if you are breast-feeding
• if you have severe ulcers in your mouth, stomach or/and bowel
• if you suffer from severe inflammation of mouth, stomach or/and bowel
Warnings and precautions
Talk to your doctor or pharmacist before you are given Methotrexate 100 mg/ml.
Take special care with Methotrexate 100 mg/ml
• 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 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 soft tissue necrosis or bone necrosis and impaired bone marrow function (leading to reduced blood cell production) can occur
• if you have had radiotherapy of the brain a leucoencephalopathy (inflammation of the brain) can occur
• if you have an impaired general condition (if you feel weak or infirm)
• if you are of advanced age
• if Methotrexate 100 mg/ml is given to very young children
• if you are dehydrated or suffer from conditions leading to dehydration (vomiting, diarrhoea, stomatitis)
• if you have inactive or chronic infections (e.g. shingles (herpes zoster), tuberculosis, hepatitis B or C), or are in contact with these infections
• if you have diabetes mellitus treated with insulin
• if you had skin problems after radiation therapy (radiation induced dermatitis) and sun-burn. These conditions can reappear under methotrexate therapy (recall-reaction).
• if you have a fast growing tumour, a tumour lysis syndrome (renal failure due to massive destruction of rapidly growing tumour cells) can occur
• if you produce black stool
Psoriatic lesions can worsen during UV-irradiation and simultaneous administration of methotrexate.
Because of the possibility of fatal or severe intoxication during methotrexate therapy medium or high doses
should only be used in patients with life-threatening tumour diseases. Rare cases of death have been reported
after methotrexate tumour therapy.
Patients undergoing methotrexate therapy should be closely monitored to prevent intoxication and to ensure fast identifying of toxic side effects.
Recommended examinations
Even if this medicine is administered at a low dosage, 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 the following examinations:
• blood tests such as blood cell counts of leucocytes, thrombocytes, erythrocytes
• kidney function tests such as creatinine
• blood tests to check liver function such as liver enzymes e.g. transaminases, hepatitis serology
• lung function tests, chest X-ray, tuberculosis test
During treatment your doctor may carry out the following examinations:
• blood tests such as blood cell counts of leucocytes, thrombocytes, erythrocytes, methotrexate serum level
• kidney function tests such as urine flow, pH value of the urine, blood (serum) tests such as creatinine, urea
• blood tests to check liver function such as liver enzymes e.g. transaminases, bilirubine
• chest X-ray
• liver biopsy
• check of mouth and throat for impairment of mucous membranes such as inflammation or ulceration Do not miss appointments for these 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 100 mg/ml
Tell your doctor if you are taking, have recently taken or might take any other medicines.
Remember to tell your doctor about your treatment with Methotrexate 100 mg/ml, if you are prescribed another medicine while the treatment is still ongoing.
It is especially important to tell your doctor if you are using:
• non-steroidal anti-inflammatory drugs (NSAIDs; medicines against “rheumatism”, e.g. indomethacin, ibuprofen)
• pain-killers such as salicylates (e.g. aspirin), amidopyrine derivatives, phenylbutazone and leflunomide
• diphenylhydantoins (e.g. phenytoin, used to treat seizures)
• barbiturates and tranquillisers (sedative agents)
• antibiotics (medicine against bacteria), e.g. tetracyclines, penicillins, chloramphenicol, cotrimoxazole, sulphonamides, trimethoprim, sulfamethoxazole
• cytostatics (medicine against cancer), e.g. doxorubicin, mercaptopurine, procarbazine, cisplatin, L-asparaginase, vincristine, cytarabine and 5-fluorouracil
• disease-modifying antirheumatic drugs (DMARD; medicines that are used to treat rheumatoid arthritis)
• probenecid (used to treat gout)
• p-aminobenzoic acid (used in sun creams)
• anti-folate medicines (e.g. nitrous oxide or co-trimoxazole)
• p-aminohippuric acid (substance to check kidney function)
• pyrimethamine (medicine against malaria)
• cholestyramine (lipid-lowering agent)
• acitretin or other retinoids (for psoriasis or skin disorders)
• theophylline (used to treat asthma)
• erythrocyte concentrates (for blood transfusion)
• nitrous oxide-based anaesthetics
• omeprazole (used to treat stomach ulcers)
• sulphasalazine (used to treat inflammation of the bowel)
• tetrahydrofolic acid preparations
• oral antidiabetics (medicines to treat diabetes)
• diuretics (increase urine output)
• hypoglycaemics (lower blood sugar levels)
• other medicines with nephrotoxic and hepatotoxic potential (incl. alcohol)
• vaccinations
• azathioprine (an immunosuppressive medicine)
• vitamin preparations containing folic acid or its derivates
• prednisolone (anti-inflammatory medicinal product)
Please note that these statements may also apply to products used some time ago or at some time in the future.
Methotrexate 100 mg/ml 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 this medicine because dehydration (reduction in body water) can increase the toxicity of methotrexate.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Do not use this medicine during pregnancy or if you are trying to become pregnant. Methotrexate can cause birth defects, harm unborn babies or cause miscarriages and so it is very important that it is not given to pregnant patients or patients planning to become pregnant. Therefore, in women of child-bearing age any possibility of pregnancy must be excluded with appropriate measures, e.g. a pregnancy test, before starting treatment. You must avoid becoming pregnant whilst taking methotrexate and for at least 6 months after treatment is stopped. Therefore you must ensure reliable contraception during this whole period (see also section “Do not use Methotrexate 100 mg/ml”).
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 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 (please see section “Do not use Methotrexate 100 mg/ml”).
Male fertility
Methotrexate temporarily affects sperm production with the potential to harm the unborn baby. 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 with this medicine. If affected you should not drive or operate machinery. If in any doubt, speak to your doctor before you drive or use machines.
Methotrexate 100 mg/ml contains sodium
This medicinal product contains 0.45 mmol (or 10.4 mg) sodium per ml. To be taken into consideration by patients on a controlled sodium diet.
3. How Methotrexate 100 mg/ml solution for injection is administered
This medicine should only be given by physicians, who are familiar with the various characteristics of the medicines and its mode of action.
This medicine must not come into contact with your eyes and/or the surface of the skin or mucosa. In the event of contamination, the affected area must be rinsed immediately with ample amount of water.
Dosage
Your doctor will decide on a suitable dose for you using current published therapy protocols for cancer treatment. 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 medicines.
Your body weight, age, general condition of health, your response to the medicine and whether other medicines are required at the same time will also influence the dose you receive.
The following table summarises recommended methotrexate doses for intravenous administration:
|
Low-dose therapy (e.g. psoriasis, psoriatic arthritis, low risk patients suffering from gynaecologic cancer [choriocarcinoma, trophoblastic disease], breast cancer, head and neck cancer, preventing relapse of acute lymphocytic leucaemia in children and adults, bladder cancer) |
Single dose below 100 mg/m2 BSA* |
|
Medium-dose therapy (e.g. high risk patients suffering from gynaecologic cancer [choriocarcinoma, trophoblastic disease], Non Hodgkins lymphoma in children and adults) |
Single dose from 100 up to 1,000 mg/m2 BSA* |
|
High-dose therapy (e.g. Non Hodgkin’s lymphoma in children, in central nervous system localised Non Hodgkin’s lymphoma, bone cancer (osteosarcoma), acute lymphocytic leucaemia in children and adults |
Single dose above 1,000 mg/m2 BSA* |
* mg/m2 BSA = milligram/square meter of body surface area
Use in children
Methotrexate should be used with caution in children. Standard therapy protocols should be consulted for dosages and method and sequence of administration.
Dosage must be carefully calculated in children.
Older people
Methotrexate should be used with extreme caution in elderly patients. A reduction in dosage should be considered. Elderly patients should be monitored closely for early signs of methotrexate toxicity.
Patients with renal/hepatic dysfunction
Care should be taken in patients with impaired liver or kidney function. Such patients should be monitored closely using regular liver and kidney function tests to avoid severe toxicity.
Method of administration
Methotrexate 100 mg/ml must be given only by injection or infusion.
Your doctor or nurse will give you Methotrexate 100 mg/ml as injection either into one of your veins (e.g. as bolus or infusion), arteries, or a muscle.
If you receive more Methotrexate 100 mg/ml than you should
Since Methotrexate 100 mg/ml will usually be given to you by a doctor or nurse under carefully controlled conditions, it is unlikely that you will be given too much or that you will miss a dose. If you have received too much of Methotrexate 100 mg/ml, or if it is suspected, that you may have received too much, appropriate action will be taken promptly by your healthcare specialist team.
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.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
All medicines can cause allergic reactions although serious allergic reactions are rare. Any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body) should be reported to a doctor immediately.
The frequency of side effects is classified into the following categories:
|
Very common |
may affect more than 1 in 10 people |
|
Common |
may affect up to 1 in 10 people |
|
Uncommon |
may affect up to 1 in 100 people |
|
Rare |
may affect up to 1 in 1,000 people |
|
Very rare |
may affect up to 1 in 10,000 people |
|
Not known |
frequency cannot be estimated from the available data |
Methotrexate is a very toxic medicine and some patients have died, or become very ill whilst being treated with it. . Because the toxic reactions can occur at any time during therapy, you should watch for any side effects and report them to your doctor as soon as possible. Your doctor must inform you of early signs and symptoms of toxicity.
The most common side effects are ulcer and inflammation of the mouth, reduced blood cell counts, nausea, vomiting and abdominal discomfort. When inflammation of the mucous membranes (stomatitis) or diarrhoea occur, therapy with methotrexate should be discontinued due to the danger of bleeding in the bowel or perforation of the bowel.
Serious side effects
If you develop any of the following side effects, contact your doctor immediately:
• inflammation of the lung with breathlessness (symptoms may be general illness; dry, irritating cough; shortness of breath, breathlessness at rest, chest pain, or fever)
• skin rashes or blistering of the skin or mucous membranes
• unusual bleeding (including vomiting blood) or bruising
• severe diarrhoea
• ulcer in mouth
• sore throat
• black or tarry stools
• blood in the urine or stools
• severe infection caused by viruses or bacteria
Other possible side effects of Methotrexate 100 mg/ml
Infections
Common: Herpes zoster Uncommon: Pneumonia Rare: Sepsis
Very rare: Virus infections (e.g. cytomegalovirus), severe other infections, fungal infections Neoplasms
Uncommon: Lymphoma
Very rare: Tumour lysis syndrome (renal failure due to massive destruction of rapidly growing tumour cells) Blood disorders
Very common: Reduced white blood cells and platelets Common: Reduced red blood cells, reduction in all blood cells Rare: Anaemia
Very rare: Abnormal low numbers of red blood cells (aplastic anaemia) abnormal low number in white blood cells such as neutrophils, eosinophils abnormal growth of lymphoctes. These blood picture changes may increase your vulnerability for infections or may lead to unusual bleeding or bruising and you may observe signs of anaemia (weakness, tiredness).
Immune system disorder
Very common: Allergic reactions, fever, inflammation of veins, decreased resistance to infection, inflammation of veins, shock Very rare: Reduced antibodies
Metabolism and endocrine disorders Uncommon: Diabetes
Not known: Malabsorption (disturbances of uptake of nutrition with consequences such as body weight loss)
Psychiatric disorders
Uncommon: Depression
Rare: Mood swings, irritability
Not known: Psychosis (severe mental illness)
Nervous system disorders
Common: Headache, dizziness, drowsiness, sleepiness
Uncommon: Seizures, leukoencephalopathy (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, poor mental function associated with confusion, forgetfulness, and difficulty concentrating
Rare: Speech disorder, subtle cognitive dysfunction (easily disturbed attention), mental disturbance, muscle weakness
Very Rare: Unusual sensations in the head, pain, paraesthesia (pins-and-needles sensation), significant intellectual deficit, dementia
Eye disorders
Rare: Impairment of vision, serious visual changes, blurred vision
Very rare: transient blindness/vision loss, swelling, inflammation of the eyelid edges, conjunctivitis (inflammation of the eye conjunctiva), unusual formation of tears, photophobia
Cardiac disorders Rare: Low blood pressure
Very rare: 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 of the lung; the pulmonary toxicity may manifest as fever, cough (especially dry and nonproductive), difficulties or increase in the frequency of breathing, chest pain, and/or abnormal findings on chest radiography and/or tests of respiratory function
Uncommon: lung fibrosis (increase in the connective tissue), fluid between the lungs and chest wall (pleural effusion)
Rare: Upper respiratory tract infection
Very rare: asthma-like symptoms (e.g. cough, difficulty breathing), pneumonia infection caused by bacteria Not known: Pulmonary oedema (fluid in the lung that may lead to difficulty breathing)
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: Melaena (red to black stools), inflammation of the mucosa in the mouth and bowel
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 Common: elevated liver enzymes
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 with liver failure Not known: reactivation of pre-existing hepatitis
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, impaired wound healing
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
Not known: exfoliative dermatitis (widespread skin rash with flaking skin), skin necrosis (loss of skin tissue), petechiae (red spots on the skin)
Musculoskeletal disorders
Uncommon'. Osteoporosis, pain in the joints, muscle pain Rare: stress fracture
Not known: 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
Rare: high level of uric acid and/or urea in the blood
Very rare: blood in the urine, elevated protein level in the urine
Pregnancy and lactation
Uncommon: Malformations of the foetus
Rare: Abortion
Very rare: death of the unborn baby
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, vaginal discharge
General disorders
Uncommon: Fever without any detectable cause Rare: Chills, malaise and undue fatigue, sweating Very rare: Sudden death
Local reactions at the injection side can occur and include effects such as burning sensation or injuries (sterile abscesses, loss of adipose tissue).
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).
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 carcinogenic risk.
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 [to be completed nationally]. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store Methotrexate 100 mg/ml
Keep this medicine out of the sight and reach 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.
Do not use this medicine after the expiry date which is stated 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 100 mg/ml contains
- The active substance is Methotrexate. Each 1 ml of this sterile solution for injection contains 100 milligrams methotrexate.
- The other ingredients are sodium hydroxide, water for injections and nitrogen.
What Methotrexate 100 mg/ml looks like and contents of the pack
Methotrexate 100 mg/ml is an orange-yellow and sterile solution in clear glass vials.
Each pack contains 1 vial of 10 or 50 ml solution.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
medac Gesellschaft fur klinische Spezialpraparate mbH Theaterstr. 6 22880 Wedel Germany
Tel.: +49 4103 8006-0 Fax: +49 4103 8006-100
This leaflet was last revised in {MM/YYYY}.
pal (Common) Methotrexate 100 mg/ml solution for injection
Date of common version: 03/2015