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231-30-84355-N LEA METHOTREXATE 25mg/ml TEVAH


09 April 2015


1. Name of the Medicinal Product
Methotrexate 25 mg/ml Injection.
2. Qualitative and Quantitative Composition
Each 1 ml contains methotrexate (present in solution as methotrexate sodium) equivalent to
25 mg anhydrous methotrexate. For the full list of excipients, see 6.1.
3. Pharmaceutical Form
Sterile solution for injection or infusion.
4. Clinical Particulars
4.1 Therapeutic Indications
Methotrexate is used for the treatment of neoplastic disease.
4.2 Posology and Method of Administration
Routes of administration: For intramuscular, intravenous (bolus injection or infusion), intrathecal,
and intra-arterial use. Methotrexate should only be administered by or under the direct
supervision of a physician experienced in cytotoxic chemistry.
Adults and Children
Dosages are based on a patients bodyweight or surface area except when administering by the
intrathecal routes when a maximum dose of 15 mg is recommended. If the patient has hepatic
or renal impairment, or haematological deficiency, then the dosage should be reduced. When
giving larger doses (more than 100 mg), the intravenous route is usually used with infusion over
a period of up to 24 hours; part of the dosage may be given as an initial rapid intravenous
Methotrexate has been used with beneficial effects in a wide variety of neoplastic diseases,
alone and in combination with other cytotoxic agents, hormones, radiotherapy or surgery.
Dosage schedules therefore vary considerably, depending on the clinical use, particularly when
intermittent high-dose regimens are followed by the administration of calcium folinate to rescue
normal cells from toxic effects.
Elderly people
Due to diminished hepatic and renal function and decreased folate stores, methotrexate should
be used with extreme caution in elderly patients. A reduction in dosage should be considered
and these patients should be closely monitored for early signs of toxicity.
The following are examples of dosage regimes that have been used for particular indications.
Choriocarcinoma and other trophoblastic tumours:
Intramuscular administration of 0.25 - 1 mg/kg to a maximum of 60 mg per dose every 48
hours (with calcium folinate rescue) for 4 doses. Repeated courses at 7 day intervals should be
given until urinary chorionic gonadotrophin levels have returned to normal. This usually requires
at least four courses of treatment. If patients have complications such as extensive metastases,
they may be treated with combinations of other cytotoxic drugs and methotrexate. Similar
doses are used for the treatment of hydatidiform mole and chorioadenoma destruens.
Leukaemia in children: To induce remissions in acute lymphocytic leukaemia, the use of a
combination of other cytotoxic drugs and corticosteroids is reported to be best.
Methotrexate 15 mg/m2, given parenterally or orally once weekly, in combination with other
drugs appears to be the treatment of choice for maintenance of drug-induced remissions.
Meningeal Leukaemia in children: Doses of up to 15 mg, intrathecally, at weekly intervals, until
the CSF appears to be normal (usually 2-3 weeks) have been found useful for the treatment of
meningeal leukaemia.
Although intravenous doses of the order of 50 mg/m2 of methotrexate do not appreciably
penetrate the CSF, larger doses of the order of 500 mg/m2 or greater do produce cytotoxic
levels of methotrexate in the CSF. This type of therapy has been used in short courses, followed
by administration of calcium folinate, as initial maintenance therapy to prevent leukaemic
invasion of the central nervous system in children with poor prognosis lymphocytic leukaemia.
Lymphoma: Non-Hodgkin’s lymphoma, e.g. childhood lymphosarcoma, has recently been
treated with 3-30 mg/kg (approximately 90-900 mg/m2) of methotrexate given by intravenous
injection and infusion followed by administration of calcium folinate with the higher doses.
Some cases of Burkitt’s lymphoma, when treated in the early stages with courses of 15 mg/m2
daily for five days, have shown prolonged remissions. Combination chemotherapy is also
commonly used in all stages of the disease.
Breast Cancer:
In advanced breast cancer, methotrexate is often given in cyclical combinations with other
cytotoxic drugs. The methotrexate is given in intravenous doses of 10-60 mg/m2. Adjuvant
therapy in early cases following mastectomy and/or radiotherapy has used similar dosage regimes.
Osteogenic Sarcoma: Adjuvant therapy to primary surgical treatment of osteosarcoma has
recently included methotrexate either alone or in cyclical combination with other drugs. Doses
have been from 20-300 mg/kg (approximately 600-9000 mg/m2) methotrexate given
intravenously and followed by calcium folinate rescue. Treatment of metastatic cases of
osteosarcoma has also employed the sole use of methotrexate.
Bladder Carcinoma: Doses of up to 100 mg of methotrexate intravenously every one or two
weeks are reported to have given encouraging results for bladder carcinoma. The results vary
from symptomatic relief to complete regressions, although these are unsustained. It is also
reported that high dosage methotrexate with calcium folinate rescue is being evaluated.
Head and Neck Cancer: Pre-operative adjuvant therapy and the treatment of advanced tumours
have used doses of 240-1080 mg/m2 methotrexate, given by intravenous infusions followed by
calcium folinate rescue. Methotrexate is also reported to have been given by intra-arterial
infusions in the treatment of head and neck cancers.
Bronchogenic Carcinoma: 20-100 mg/m2 methotrexate given by intravenous infusion has been
used in cyclical combinations for the treatment of advanced tumours. High doses of
methotrexate, followed by calcium folinate rescue have also been used as the sole treatment.
4.3 Contraindications
Profound impairment of renal or hepatic function or haematological impairment.
Alcoholism. Liver disease including alcoholic liver disease, fibrosis, cirrhosis, recent or active
hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency
Pre-existing blood dyscrasias, such as bone marrow hypoplasia, anaemia, leucopenia or
Methotrexate is contra-indicated in pregnant patients. Because of the potential for serious
adverse reactions from methotrexate in breast fed infants, breast-feeding is contra-indicated in
women taking methotrexate.
Patients with a known allergic hypersensitivity to methotrexate or any of the excipients in the
formulation should not receive methotrexate.
Diluents containing preservatives must not be used for intrathecal or high dose methotrexate
4.4. Special Warnings and Precautions for Use
Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.
Because of the possibility of fatal or severe toxic reactions, the patient should be fully informed
by the physician of the risks involved and be under his constant supervision.
Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur
and deaths have been reported.
Potentially fatal opportunistic infections, including Pneumocystis carinii pneumonia, may occur
with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility
of Pneumocystis carinii pneumonia should be considered.
Pulmonary signs and symptoms, e.g. a dry non-reproductive cough, fever, cough, chest pain,
dyspnoea, hypoxemia and an infiltrate on chest x-ray, or a non-specific pneumonitis may also
be indicative of a potentially dangerous lesion and require interruption of treatment and careful
investigation. Pulmonary lesions can occur at all dosages. Methotrexate induced lung disease may
occur acutely at any time during therapy and has been reported at doses as low as 7.5 mg/week.
It is not always fully reversible. Infection (including pneumonia) needs to be excluded.
Patients should be monitored for pulmonary signs and symptoms at each follow up visit.
Patients should be informed of the risk of pneumonitis and advised to contact their doctor
immediately should they develop a persistent cough or dyspnoea.
Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough
investigation should be made to exclude infection. If methotrexate induced lung disease is
suspected, treatment with corticosteroids should be initiated and treatment with methotrexate
should not be restarted.
Deaths have been reported with the use of methotrexate in the treatment of malignancy,
therefore it should only be used in life threatening neoplastic diseases.
1. Full blood counts should be closely monitored before, during and after treatment. Any
profound drop in white-cell or platelet counts should result in immediate withdrawal of the drug
and appropriate supportive therapy (see section 4.8). Patients should be advised to report all
signs and symptoms suggestive of infection.
2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy.
Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since
changes may occur without previous signs of gastrointestinal or haematological toxicity, it is
imperative that hepatic function be determined prior to initiation of treatment and monitored
regularly throughout therapy. If substantial hepatic function abnormalities develop,
methotrexate dosing should be suspended for at least 2 weeks. Special caution is indicated in
the presence of pre-existing liver damage or impaired hepatic function. Concomitant use of

other drugs with hepatotoxic potential (including alcohol) should be avoided.
3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or
congenital anomalies. Therefore it is not recommended in women of childbearing potential
unless there is appropriate medical evidence that the benefits can be expected to outweigh the
considered risks. Pregnant psoriatic patients should not receive methotrexate.
4. Renal function should be closely monitored before, during and after treatment. Caution
should be exercised if significant renal impairment is disclosed. Reduce dose of methotrexate in
patients with renal impairment. High doses may cause the precipitation of methotrexate or its
metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH
6.5 – 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets
every three hours) or acetazolamide (500 mg orally four times a day) is recommended as a
preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the
presence of impaired renal function may result in accumulation of toxic amounts or even
additional renal damage.
5. Symptoms of gastro-intestinal toxicity, usually first manifested by diarrhoea and ulcerative
stomatitis, necessitate interruption of therapy otherwise haemorrhagic enteritis and death from
intestinal perforation may occur.
6. Methotrexate affects gametogenesis during the period of its administration and may result
in decreased fertility which is thought to be reversible on discontinuation of therapy.
Conception should be avoided during the period of methotrexate administration and for at
least 6 months thereafter. Patients and their partners should be advised to this effect.
7. The immunological response to concurrent vaccination could be decreased, as methotrexate
has some immunosuppressive activity. A severe reaction could result from the concomitant use
of a live vaccine, and it is therefore not generally recommended. There have been reports of
disseminated vaccinia infections after smallpox immunisation in patients receiving
methotrexate therapy.
8. Patients with pleural effusions or ascites should have these drained if appropriate before
treatment and their plasma methotrexate levels monitored, or treatment should be withdrawn.
The reason being that methotrexate exits slowly from third party compartments (e.g. pleural
effusions, ascites). This results in a prolonged terminal half-life and unexpected toxicity.
9. Deaths have been reported with the use of methotrexate. Serious adverse reactions
including deaths have been reported with concomitant administration of methotrexate (usually
in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).
10. Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole
has been reported to cause an acute megaloblastic pancytopenia in rare instances.
11. Systemic toxicity may occur following intrathecal administration. Blood counts should be
monitored closely.
12. A chest X-ray is recommended prior to initiation of methotrexate therapy.
13. If acute methotrexate toxicity occurs, patients may require folinic acid.
Folate deficiency states may increase methotrexate toxicity.
Methotrexate has a high potential toxicity, usually dose related, and should be used only by
physicians experienced in antimetabolite chemotherapy, in patients under their constant
supervision. The physician should be familiar with the various characteristics of the drug and its
established clinical usage.
Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, a
chest x-ray, assessment of renal function, liver function and blood elements should be made by
history, physical examination and laboratory tests. Patients undergoing therapy should be
subject to appropriate supervision every 2-3 months so that signs of possible toxic effects or
adverse reactions may be detected and evaluated with minimal delay. Renal function and full
blood counts should be closely monitored before, during and after treatment.
It should be noted that intrathecal doses are transported into the cardiovascular system and
may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in
patients with renal dysfunction, ascites or other effusions due to prolongation of serum
Carcinogenesis, mutagenesis and impairment of fertility: Animal carcinogenicity studies have
demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has
been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in
humans, these effects are transient and reversible. In patients treated with methotrexate,
evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.
Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual
dysfunction and amenorrhoea in humans, during and for a short period after cessation.
In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans.
Therefore, the possible risks of effects on reproduction should be discussed with patients of
child-bearing potential (see ‘warnings’).
Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia,
pancytopenia, leucopenia, neutropenia and/or thrombocytopenia. Haematopoietic suppression
caused by methotrexate may occur abruptly and with apparently safe dosages. Methotrexate
should be used with caution, if at all in patients with malignancy and pre-existing
haematopoietic impairment. In the treatment of neoplastic diseases, methotrexate should be
continued only if the potential benefit outweighs the risk of severe myelosuppression.
It is essential that the following laboratory tests are included regularly (every 2-3 months) in
the clinical evaluation and monitoring of patients receiving methotrexate: complete
haematological analysis, urinalysis, renal function tests, liver function tests, chest X-ray and,
when high doses are administered, determination of plasma levels of methotrexate.
The purpose is to determine any existing organ dysfunction or system impairment. The tests
should be performed prior to therapy, at appropriate periods during therapy and after
termination of therapy.
Liver biopsy may be considered after cumulative doses>1.5 g have been given, if hepatic
impairment is suspected.
Methotrexate is bound in part to serum albumin after absorption, and toxicity may be
increased because of displacement by certain drugs such as salicylates, sulphonamides,
phenytoin, and some antibacterials such as tetracycline, chloramphenicol and
para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether
antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance
of these findings is established.
Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.
Methotrexate should be used with extreme caution in patients with the presence of infection,
haematological depression, renal impairment, peptic ulcer, ulcerative colitis, ulcerative
stomatitis, diarrhoea, debility, and also in young children and the elderly. If profound
leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation
of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow
depression, blood or platelet transfusions may be necessary.
Methotrexate therapy in patients with impaired renal function should be undertaken with
extreme caution, and at reduced dosages because impairment of renal function will decrease
methotrexate elimination.
Since it is reported that methotrexate may have an immunosuppressive action, this factor must
be taken into consideration in evaluating the use of the drug where immune responses in a
patient may be important or essential.
In all instances where the use of methotrexate is considered for chemotherapy, the physician
must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse
reactions. Toxic effects may be related in frequency and severity to dose or frequency of
administration, but has been seen at all doses and can occur at any time during therapy. Most
adverse reactions are reversible if detected early. When such reactions do occur, the dosage
should be reduced or discontinued and appropriate corrective measures should be taken. If
methotrexate therapy is reinstituted, it should be carried out with caution, with adequate
consideration of further need for the drug, and with increased alertness as to possible
recurrence of toxicity.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue
necrosis and osteonecrosis.
If vomiting resulting in dehydration happens, methotrexate should be discontinued until
recovery occurs.
Like other cytotoxic drugs, methotrexate may induce “tumour lysis syndrome” in patients with
rapidly growing tumours. Appropriate supportive and pharmacologic measures may prevent or
alleviate this condition.
Severe, occasionally fatal, skin reactions such as Stevens-Johnson Syndrome, toxic epidermal
necrolysis (Lyell’s syndrome) and erythema multiforme have been reported within days of
administering single or multiple doses of methotrexate.
Acutely, liver enzyme elevations are frequently seen. These are usually transient and
asymptomatic, and do not appear predictive of subsequent hepatic disease. Persistent liver
abnormalities and/or decrease of serum albumin may be indicators of serious liver toxicity.
Liver biopsy after sustained use often shows histological changes, and fibrosis and cirrhosis
have been reported.
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 other cytotoxic therapy.
The use of methotrexate high-dose regimens recommended for osteosarcoma requires
meticulous care. High dosage regimens for other neoplastic diseases are investigational and a
therapeutic advantage has not been established.
Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to
renal function including adequate hydration, urine alkalinisation, and measurement of serum
methotrexate and renal function are recommended.


Read all of this leaflet carefully before you start using this medicine
because it contains important information for you .
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you get any of the 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 is and what it is used for
2. What you need to know before you receive Methotrexate
3. How to receive Methotrexate
4. Possible side effects
5. How to store Methotrexate
6. Contents of the pack and other information



Methotrexate is an anti-metabolite drug that affects cell growth.
Methotrexate is used in the treatment of cancer. It prevents cancer cells
from growing and eventually kills them.
Methotrexate may be given on its own or in combination with other drugs.
Ask your doctor or nurse if you need additional information.



Do not take Methotrexate if you:
• are allergic to Methotrexate sodium or any of the other ingredients of
this medicine (listed in section 6)
• have severe kidney problems
• have any liver problems including liver disease, liver fibrosis (fibrous
tissue in the liver), recent or active hepatitis (inflammation of the liver)
• have any blood problems, which may be characterised by fever or chills,
sore throat, ulcers in the mouth or throat, unusual tiredness or weakness,
unusual bleeding or unexplained bruising or an abnormal blood count
• have an infectious disease
• have a problem with your immune system
• are pregnant, planning to become pregnant or breast-feeding
• suffer from alcoholism.
Warnings and precautions
Talk to your doctor before taking Methotrexate if you:
• have ulcers in the stomach, lining of the large intestine (ulcerative colitis)
or mouth and lips (ulcerative stomatitis)
• have an infection
• are suffering from diarrhoea
• are weak or feeble
• are a young child or elderly
• have excess fluid between the lungs and chest wall or abdominal
swelling (ascites)
• are about to have a vaccine
• are having radiotherapy (risk of tissue and bone damage may be
• suffer from foliate deficiency (a lack of folic acid, which is a type of
B vitamin)
• have liver problems
• kidney problems.
Other medicines and Methotrexate
Talk to your doctor or nurse if you are taking, have recently taken or might
take any of the following:
• Non Steroidal Anti Inflammatory Drugs (NSAIDs) e.g. aspirin, ibuprofen,
• aspirin or similar medicines (known as salicylates)
• probenecid (used to treat gout)
• broad-spectrum antibiotics e.g. penicillin
• tetracycline antibiotics e.g. oxytetracycline, doxycycline
• omeprazole and pantoprazole (used to help reduce the production of
stomach acid)
• phenylbutazone or leflunomide (used to treat rheumatic disorders)
• azathioprine (an immunosuppressive drug)
• sulfasalazine (used to treat ulcerative colitis)
• vitamin preparations containing folic acid or its derivatives or vitamin A
related compounds
• calcium folinate
• p-aminobenzoic acid (used in sun creams)
• cisplatin (used to treat cancer)
• sulphonamides e.g. co-trimoxazole
• chloramphenicol
• diuretics (“water tablets”) e.g. furosemide
• acidic anti-inflammatory drugs e.g. ketoprofen
• diphenylhydantoins e.g. phenytoin (used to treat epilepsy)
• hypoglycaemics (used to lower blood sugar levels)
• trimethoprim (used to treat infections)
• nitrous oxide (an anaesthetic)
• retinoids such as acitretin (used to treat psoriasis (patches of thickened
and sore skin) or skin disorders)
• theophylline (used to treat asthma)
• phenytoin (medicine often used to treat epilepsy)
• other drugs that may cause damage to your kidney
• other drugs that may cause damage to your liver.
Please tell your doctor or nurse if you are taking or have recently taken any
other medicines, including medicines obtained without a prescription.
Receiving Methotrexate with food and drink
• DO NOT drink alcohol whilst receiving methotrexate therapy.
Pregnancy, breast-feeding and fertility
• Methotrexate can harm unborn babies. If you are pregnant or
breast-feeding, think you may be pregnant or are planning to have a
baby, ask your doctor or nurse for advice before taking this medicine.
• You should avoid becoming pregnant or fathering children for at least
three months after stopping your treatment with Methotrexate due to
the temporary effect of Methotrexate on sperm and egg production.
Driving and using machines
Methotrexate is not expected to affect your ability to drive or operate



Your medicine will be administered by a doctor or nurse as an injection
either, into a vein or artery, or into a muscle. Methotrexate 25 mg/ml
Injection can also be given into your spine.
You may have tests before, during and after your treatment to ensure that
methotrexate is working properly and your kidneys are getting rid of any
of the drug that is not required. Do not miss appointments for these tests.
• Adults and children:
The dosage of Methotrexate varies from person to person depending on
your body weight and surface area in square metres (m2) and the way
that you are given the drug.
The amount of Methotrexate you are given will also depend on the
condition being treated and whether Methotrexate is being given on its
own or with other medicines.
Your doctor will decide on the correct amount of Methotrexate to give you.
• Elderly patients:
You will receive a lower dose than those usually used. Your doctor will
want to monitor you for side effects.


231-30-84355-N LEA METHOTREXATE 25mg/ml TEVAH


09 April 2015

If you receive more Methotrexate than you should
As a doctor or nurse will be giving you your medicine, it is unlikely that
you will receive an incorrect dose. Tell your doctor or nurse if you have
any concerns about the amount of medicine that you receive.
If you have any further questions on the use of this product, ask your
doctor, pharmacist or nurse.



Like all medicines, this medicine can cause side effects, although not
everybody gets them.
Methotrexate is a very toxic medicine and patients have died, or become
very ill, whilst being treated with it. During treatment you should watch
for any side effects and report them to the doctor.
Methotrexate may affect some of the other cells in your body as well as
the cancer cells and you will probably suffer from some side effects. Side
effects increase with a higher dose of Methotrexate.
Tell your doctor or nurse immediately if any of the following happen;
these are rare but serious side effects:
• difficulty breathing and swelling of the lips, face and neck, rash, itching,
shortness of breath, abnormal heart beat, low blood pressure (feeling
dizzy or faint)
• severe blistering or bleeding of the lips, eyes, nose, mouth or genitals
• severe skin reactions causing skin scaling, blistering and peeling.
Methotrexate can reduce your resistance to infection:
• in some cases, patients receiving treatment with Methotrexate have
developed opportunistic infections (infections caused by organisms that
usually do not cause disease in a person with a healthy immune system,
but can affect people with a poorly functioning or suppressed immune
system); these can sometimes be serious and potentially fatal.
The most common side effects are:
• nausea
• a painful or swollen stomach
• soreness or ulceration of the mouth and lips (ulcerative stomatitis)
• leucopenia (a blood disorder that may be characterised by fever or
chills, sore throat or ulcers in your mouth or throat).
Methotrexate may also cause the following side effects:
• itching, rash, hives, discolouration of the skin, sensitivity to light, hair
loss, redness, bruising, acne, boils, aggravation of psoriasis (patches of
thickened and sore skin), appearance of nodules (small lumps) on the
skin, chills, fever, muscle or joint pain, bone fractures
• bone marrow depression (characterised by abnormal levels of blood
cells, bruising or bleeding, pale skin, weakness or breathlessness, fever
or chills, sore throat or ulcers in your mouth or throat, infection, blood
poisoning), lymph gland problems, immune system problems,
inflammation of the blood vessels, breaking down of cells, abnormal
red blood cells
• ulcers / bleeding of the lining in the nose, mouth, gums, throat, lips,
gut and genitals, inflammation of gums (gingivitis), problems with food
absorption, dilation of the colon associated with stomach bloating, dark
or tarry stools, vomiting of blood, nausea, vomiting, diarrhoea, loss of
• difficulty in swallowing accompanied by earache and swollen glands,
sore throat
• inflammation or ulceration of the mouth e.g. mouth ulcers and cold
• blurred vision, conjunctivitis ("pink eye", where the eyelids become
reddened, swollen and sticky), loss of vision, eye irritation
• diabetes, metabolic changes
• headaches, drowsiness, dizziness, a general feeling of being unwell,
tiredness, decline in mental ability, changes in mood or behaviour,
unusual sensations of the skull, loss of movement, impaired movement,
problems with speech/language, fits, inflammation of the brain,
abnormal behaviour, abnormal reflexes
• chest pain, fluid around the heart, low blood pressure, blood clots,
inflammation of a vein associated with blood clots, blood clots in the
brain, eyes and lungs, deep vein thrombosis
• accumulation of fluid in the lungs, lung infection, scarring of the lungs,
thickening of the lining around the lungs, pain when breathing,
breathing problems, coughing and wheezing
• loss of kidney function, kidney damage, lack of filtering of the blood by
the kidneys, pain or difficulty passing water, cystitis (infection of the
bladder which causes frequent passing of water and passing water with
a burning sensation), blood in the urine
• abnormal liver enzymes, high level of a protein called albumin in the
blood, liver wasting, death of liver cells, inflammation of the liver, fatty
liver deposits, liver cirrhosis (a condition where cells of the liver die and
are replaced by hard fibrous tissue)
• reduced fertility, problems with periods or no periods, loss of interest
in sex or impotence, inflammation of the vagina, vaginal discharge,
vaginal ulcers.
Other side effects may occur that can only be detected by your doctor,
these include certain blood disorders, changes in liver or kidney function
or bone density.
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:
By reporting side effects you can help provide more information on the
safety of this medicine.


Drugs such as salicylates, sulphonamides, tetracyclines, chloramphenicol, diuretics,
p-aminobenzoic acid, acidic anti-inflammatory drugs, diphenylhydantoins, hypoglycaemics may
displace methotrexate, which is extensively protein bound, increasing the potential for toxicity
when given concurrently. Concomitant use of other drugs with nephrotoxic or hepatotoxic
potential (including alcohol) should generally be avoided, unless considered clinically justified, in
which case the patient should be closely monitored.
The response to methotrexate may be altered if vitamin preparations which contain folic acid or
its derivatives are also being taken. High doses of calcium folinate may reduce the efficacy of
intrathecally administered methotrexate.
If methotrexate is given prior to or concomitantly with NSAID’s, including salicylates, extreme
caution should be exercised as there have been reports of severe methotrexate toxicity and even
death due to reduced methotrexate excretion. These drugs have been reported to reduce the
tubular secretion of methotrexate in an animal model and thereby may enhance its toxicity. It is
recommended that methotrexate dosage be carefully controlled during treatment with NSAIDs.
However, patients using constant dosage regimens of NSAIDs have received concurrent doses of
methotrexate without problems observed.
Renal tubular transport is also diminished by probenecid, penicillins, and proton-pump inhibitors
(e.g. omeprazole, pantoprazole) which may result in potentially toxic methotrexate levels. The use
of methotrexate with these drugs should be carefully monitored. Haematologic and
gastrointestinal toxicity have been observed in combination with high and low dose methotrexate.
It has been reported rarely that the use of folate antagonists e.g. trimethoprim, co-trimoxazole,
when given concomitantly with methotrexate may cause bone marrow depression, acute
megaloblastic pancytopenia. Methotrexate-induced stomatitis and other toxic effects may be
increased by the use of nitrous oxide. Methotrexate should be used with caution in patients
taking drugs with an anti-folate potential.
The potential for increased hepatotoxicity when methotrexate is administered with other
hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such
cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential
hepatotoxic agents (e.g. alcohol, leflunomide, azathioprine, sulfasalazine, retinoids) should
generally be avoided, unless clinically justified, in which case the patient should be closely
monitored for possible increased risk of hepatotoxicity.
Enhancement of nephrotoxicity may be seen when high-dose methotrexate is administered in
combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).
Existing data suggests that etretinate is formed from acitretin after ingestion of alcoholic
beverages. However, the formation of etretinate without concurrent alcohol intake cannot be
excluded. Methotrexate serum levels may be increased by etretinate (acitretin metabolite) and
severe hepatitis has been reported following concomitant use. Consequently, the concomitant
use of methotrexate and acitretin should be avoided.
Oral antibiotics, such as tetracycline, chloramphenicol, and non-absorbable broad spectrum
antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic
circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be
monitored when used concurrently with methotrexate.
4.6. Fertility, pregnancy and lactation
Abortion, foetal death, and/or congenital anomalies have occurred in pregnant women receiving
methotrexate, especially during the first trimester of pregnancy. Therefore it is not recommended
in women of childbearing potential unless the benefits can be expected to outweigh the
considered risks. Women of childbearing potential should not be started on methotrexate until
pregnancy is excluded. If the drug is used during pregnancy for antineoplastic indications, or if
the patient becomes pregnant while taking this drug, the patient should be informed of the
potential hazard to the foetus.
Methotrexate affects spermatogenesis and oogenesis during the period of its administration
which may result in decreased fertility. Defective oogenesis or spermatogenesis, transient
oligospermia, menstrual dysfunction have been reported in patients receiving methotrexate. To
date, this effect appears to be reversible on discontinuing therapy. Conception should be avoided
for at least 3 months after treatment with methotrexate has ceased. Patients receiving
methotrexate and their partners should be advised appropriately.
Methotrexate has been detected in human breast milk and is contra-indicated during
4.7. Effects on ability to drive and use machines
Not applicable
4.8. Undesirable effects
The most common adverse reactions include ulcerative stomatitis, leucopenia, nausea and
abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred.
Others reported are eye-irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia,
chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. In
general, the incidence and severity of side-effects are considered to be dose-related.
Opportunistic infections (sometimes fatal) have been reported in patients receiving methotrexate
therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the
most common. Other reported infections include pneumonia, nocardiosis, histoplasmosis,
cryptococcosis, Herpes zoster, Herpes simplex hepatitis and disseminated Herpes simplex.
Conjunctivitis and serious visual changes of unknown etiology have been reported.
Additional reactions related to or attributed to the use of methotrexate such as osteoporosis,
stress fractures, nodulosis, reversible lymphomas, tumour lysis syndrome, abnormal (usually
megaloblastic) red cell morphology, precipitation of diabetes, other metabolic changes,
anaphylactoid reactions and sudden death have been reported.
Adverse reactions for the various systems are as follows:
Skin: Stevens-Johnson Syndrome, toxic epidermal necrolysis (Lyell’s Syndrome), erythematous
rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis,
telangiectasia, acne, furunculosis, erythema multiforme. Lesions of psoriasis may be aggravated
by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely
painful erosion of psoriatic plaques have been reported. The recall phenomenon has been
reported in both radiation and solar damaged skin.

The vials or ampoules should be stored below 25°C in the original
Do not use this medicine after the expiry date that is stated on the outer
packaging. The expiry date refers to the last day of that month. Any
unused solution should be discarded using the appropriate precautions.


What Methotrexate Injection contains:
• The active ingredient is Methotrexate sodium, 25 mg/ml.
• The other ingredients are sodium chloride, sodium hydroxide,
hydrochloric acid and water for injections.
What Methotrexate Injection looks like and contents of the pack:
• Methotrexate Injection is available as a sterile solution for injection or
• The 25 mg/ml strength is available in ampoules containing either 1 ml
or 2 ml (in a pack of 5) of injection. 25 mg/ml strengths are available
in vials containing 2, 4, 8, 20 or 40 ml of injection.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation holder: TEVA UK Limited, Eastbourne, BN22 9AG.
Company responsible for manufacture is Pharmachemie B.V., Haarlem,
The Netherlands.
This leaflet was last revised: February 2015
PL 00289/0466

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis,
abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic
changes, and sudden death have been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme


In post-marketing experience, overdose with methotrexate has generally occurred with oral and
intrathecal administration, although intravenous and intramuscular overdosage have also been
Symptoms of intrathecal overdose are generally CNS symptoms, including headache, nausea and
vomiting, seizure or convulsion, and acute toxic encephalopathy. In some cases, no symptoms
were reported. There have been reports of death following intrathecal overdose. In these cases,
cerebellar herniation associated with increased intracranial pressure, and acute toxic
encephalopathy have been reported.
Calcium folinate is the antidote for neutralising the immediate toxic effects of methotrexate on
the haematopoietic system. Where large doses or overdoses are given, calcium folinate may be
administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg
intramuscularly every 6 hours for 4 doses. Where average doses of methotrexate appear to have
an adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6 hours for 4
doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal
to or higher than, the offending dose of methotrexate and should be administered as soon as
possible; preferably within the first hour and certainly within 4 hours after which it may not be
Other supporting therapy such as blood transfusion and renal dialysis may be required. Calcium
folinate administration should begin as promptly as possible. As the time interval between
methotrexate administration and calcium folinate initiation increases, the effectiveness of calcium
folinate in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration
is essential in determining the optimal dose and duration of treatment with calcium folinate.
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
Following intrathecal overdose, CSF drainage may remove up to 95% of the dose if commenced
within 15 minutes of administration, although this falls to 20% after 2 hours. For intrathecal
doses over 100 mg, ventriculolumbar perfusion should accompany CSF drainage. In addition,
high dose systemic calcium folinate or alkaline diuresis may be required.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: LO1B A01 Folic acid analogues
Methotrexate, a derivative of folic acid, belongs to the class of cytotoxic agents known as
antimetabolites. It acts principally during the “S” phase of cell division, by the competitive
inhibition of the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate
to tetrahydrofolate, a necessary step in the process of DNA synthesis and cellular replication.
5.2. Pharmacokinetic Properties
Methotrexate distributes rapidly following a bolus intravenous injection; its disappearance from
the plasma compartment is a triphasic: t1/2 (alpha) = 0.25-0.7 hour; t1/2 (beta) = 2.0-3.5
hours; t1/2 (gamma) = 10-15 hours. The initial plasma half-life value is often obscured because
methotrexate is infused over 2 to 12 hour periods.
Methotrexate metabolites account for less than 10% of the total dose if the drug is given
intravenously at 30 mg/m2.
The two major metabolites are 2,4-diamino-N10-methylpteroic acid (DAMPA) and
7-hydroxy-methotrexate (7-OH MTX). Both metabolites are biologically inactive. The 7-OH
MTX in the kidney tubules may contribute to nephrotoxicity especially with high-dose therapy.
Under conditions of normal renal function, drug clearance from plasma is 103 ml/min/m2.
Young children are able to tolerate considerably more systemic methotrexate, presumably
because of improved renal clearance.
Methotrexate is concentrated in the liver and the bile, and can reach bile: plasma ratios as high
as 200:1. However, the actual amount of methotrexate excreted by this route has been reported
to be only 6.3% because most biliary methotrexate is reabsorbed from the GI tract.
With intrathecal administration, the slow rate of release of methotrexate from the CSF is rate
controlling, therefore the elimination from the body is delayed, t1/2 (beta) for methotrexate
following intrathecal administration is 5.2- 7.8 hours. The terminal elimination phase is greatly
prolonged (t1/2 (gamma) = 52-78 hours).
Methotrexate is distributed mainly in the extracellular spaces but a proportion penetrates cell
membranes and is strongly bound to dihydrofolate reductase. About 50% is bound to plasma
proteins. Bound methotrexate may be retained in the body for many months.
5.3 Pre-clinical Safety Data
Preclinical information has not been included because the safety profile of methotrexate has
been established after many years of clinical use. Please refer to section 4.
6. Pharmaceutical Particulars

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea,
haematemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity
resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic
cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to
malabsorption or toxic megacolon. In rare cases the effect of methotrexate on the intestinal
mucosa has led to malabsorption or toxic megacolon.

Mixed injections should be avoided.

6.1 List of Excipients
Sodium chloride, Sodium hydroxide, Hydrochloric acid (1:20), Water for Injection.
6.2 Incompatibilities
6.3 Shelf Life
36 months.
6.4. Special Precautions for Storage
Store below 25°C in the original package.
6.5. Nature and Contents of Container
For Methotrexate 25 mg/ml Injection:

Urogenital system: High dose methotrexate therapy may result in renal failure and uraemia.
Other reactions reported to occur include cystitis, azotemia, dysuria, severe nephropathy,
haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual
dysfunction, infertility, abortion, foetal defects. Vaginitis, vaginal discharge, nephropathy and
vaginal ulcers.

Clear Type Ι glass ampoules in 1 ml or 2 ml sizes (in a pack of 5), or Clear Type Ι glass vials with
elastomeric closures in 2 ml, 4 ml, 8 ml, 20 ml and 40 ml sizes.

Pulmonary system: Acute or chronic interstitial pneumonitis, often associated with blood
eosinophilia, may occur and deaths have been reported (see Section 4.4 Warnings and
Precautions for Use). After oral and intrathecal use, acute pulmonary oedema has been reported.
Pulmonary fibrosis, respiratory failure and chronic interstitial pulmonary disease have been
reported. After high doses, pleuritic pain and pleural thickening have been reported.

Methotrexate may be diluted with the following infusion fluids:

Central nervous system: Observed effects include headaches, blurred vision and drowsiness.
Occasionally after low doses it is reported that short lived subtle cognitive dysfunction,
alterations in moods and unusual cranial sensations may be observed. Higher doses occasionally
result in hemiparesis, paresis, speech impairment including dysarthria and aphasia, and
convulsions. Following high intravenous doses or low doses of methotrexate following
cranial-spinal radiation, leucoencephalopathy has been reported. Convulsion, paresis,
Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal
Other reactions related to, or attributed to the use of methotrexate such as pneumonitis,
metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue
cells and even sudden death have been reported.
Serious neurotoxicity, frequently manifested as generalised or focal seizures has been reported
with unexpectedly increased frequency among paediatric patients with acute lymphoblastic
leukaemia who were treated with intermediate-dose intravenous methotrexate (1 gm/m2).
Symptomatic patients were commonly noted to have leucoencephalopathy and/or
microangiopathic calcifications on diagnostic imaging studies. Chronic leucoencephalopathy has
also been reported in patients who received repeated doses of high-dose methotrexate with
calcium folinate rescue even without cranial irradiation. Discontinuation of methotrexate does
not always result in complete recovery.
A transient acute neurological syndrome has been observed in patients treated with high dosage
regimens. Manifestations of this neurological syndrome may include behavioural abnormalities,
focal sensorimotor signs, including transient blindness or vision loss, and abnormal reflexes. The
exact cause is unknown.


Adverse reactions following intrathecal methotrexate are generally classified into three groups;
acute, subacute and chronic. The acute form is a chemical arachnoiditis manifested by headache,
back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually
transient, paraparesis/paraplegia associated with involvement with one or more spinal nerve
roots, nerve palsies, and cerebellar dysfunction. The chronic form is a leucoencephalopathy
manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia,
somnolence, coma and rarely, death. This central nervous system toxicity can be progressive.
There is evidence that the combined use of cranial radiation and intrathecal methotrexate
increased the incidence of leucoencephalopathy. Signs of neurotoxicity (meningeal irritation,
transient or permanent paresis, encephalopathy) should be monitored following intrathecal
administration of methotrexate.

Blood: Bone marrow depression is a common effect of methotrexate therapy and can occur
abruptly, resulting in thrombocytopenia, anaemia or leucopenia. Infection (e.g. pneumonia) or
septicaemia and haemorrhage from various sites may result. Aplastic anaemia, pancytopenia and
neutropenia, lymphadenopathy, lymphoproliferative disorders (including reversible) have been
reported, as has hypogammaglobulinaemia.

Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, decrease in serum
albumin, acute liver atrophy, necrosis, acute hepatitis, fatty metamorphosis, periportal fibrosis or
cirrhosis or death may occur, usually following chronic administration.


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


4.5. Interactions with other medicinal products and other forms of interaction

Cardiac: Pericarditis, pericardial effusion, hypotension, and thromboembolic events including
arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein
thrombosis and pulmonary embolus.

Not all pack sizes may be marketed.
6.6. Instruction for Use and Handling (and Disposal)
0.9 % sodium chloride, glucose, sodium chloride and glucose. Solutions are stable for up to
24 hours when stored at 2 - 8°C.
Discard any unused solution.
Other drugs should not be mixed with methotrexate in the same infusion container.
As with all cytotoxic preparations, special precautions should be taken for safe handling and
disposal and only trained personnel should prepare the drug. Preparation should be performed in
a designated area ideally in a vertical laminar flow hood, with the work surface covered with
disposable plastic-backed absorbentpaper.
In the event of contact with either the eyes or skin, wash thoroughly with water and seek
medical advice. Seek immediate medical attention if the drug is ingested, or if there is a danger
of systemic absorption of significant quantities of methotrexate, by any route, as calcium folinate
cover will be required.
Adequate protective clothing should be worn, such as PVC gloves, safety glasses, disposable
gowns and masks. It is recommended that luer lock fittings are used in the assembly of syringes
and giving sets to avoid leakage.
All used material, needles, syringes, vials and other items which have come into contact with
cytotoxic drugs should be incinerated. Excreta should be similarly treated.
Pregnant staff should not be involved in the handling of cytotoxic preparations.
7. Marketing Authorisation Holder
TEVA UK Limited, Eastbourne BN22 9AG.
8. Marketing Authorisation Number
PL 00289/0466
9. Date of First Authorisation/Renewal of Authorisation
10. Date of (Partial) Revision of the Text
February 2015


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