Mexat is indicated in the treatment of:
• acute lymphocytic leukaemia
• prophylaxis of meningeal leukaemia
• Non‐Hodgkin’s Lymphomas
• osteogenic sarcoma
• adjuvant and in advanced disease of breast cancer
• metastatic or recurrent head and neck cancer
• choriocarcinoma and similar trophoblastic diseases
• advanced cancer of urinary bladder.

Treatment should be initiated by or occur in consultation with a doctor with significant experience in
cytostatic treatment. Methotrexate can be administered intramuscularly, intravenously, intra‐arterial or intrathecally. The
dosage is generally calculated per m2 body surface area or body weight. Doses of over 100mg
Methotrexate always require subsequent administration of Folinic Acid (See Calcium Folinate
Rescue).
The application and dosage recommendations for the administration of Methotrexate for different
indications varies considerably. Some common dosages which have been used in different indications
are given below. None of these dosages can currently be described as standard therapy. Since the
application and dosage recommendations for therapy with Methotrexate at high and low dosages
vary, only the most commonly used guidelines are given. Current published protocols should be
consulted for dosages and the method and sequence of administration.
Methotrexate can be given as convention low dose therapy, intermediate dose therapy, high dose
therapy and intrathecal administration.
Conventional low dose therapy: 15‐50mg/m2 body surface area per week intravenously or
intramuscularly in one or more doses. 40‐60mg/m2 body surface area (for head and neck cancer)
once weekly as intravenous bolus injection.
Intermediate dose therapy: Between 100mg/m2 to 1000mg/m2 body surface area in single‐dose. In
advanced squamous epithelial and bladder cancer, intermediate doses of Methotrexate up to
100‐ 200mg/m2 can be used. (See Calcium Folinate Rescue).
High dose therapy: In several malignant diseases, including malignant lymphoma, acute lymphatic
leukaemia, osteogenic sarcoma and metastatic choriocarcinoma, doses of 1000mg Methotrexate or
more per m2 body surface area may be used, administered over a 24‐hour period. Administration of
Folinic acid must begin with 10‐15mg (6‐12mg/m2) to be given 12‐24 hours after starting
Methotrexate treatment (Further refer to therapy protocols, See Calcium Folinate Rescue).
Calcium Folinate Rescue
Since the Calcium Folinate Rescue dosage regimen depends heavily on the posology and method of
the intermediate or high‐dose Methotrexate administration, the Methotrexate protocol will dictate
the dosage regimen of Calcium Folinate Rescue. Therefore, it is best to refer to the applied
intermediate or high dose Methotrexate protocol for posology and method of administration of
Calcium Folinate.
In addition to Calcium Folinate administration, measures to ensure the prompt excretion of
Methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the
Calcium Folinate Rescue treatment. Renal function should be monitored through daily
measurements of serum creatinine.

Adults
Acute lymphocytic leukaemias (ALL)
In low doses, Methotrexate is applied within the scope of complex therapy protocols for maintaining
remission in adults with acute lymphocytic leukaemias. Normal single doses lie within the range of
20‐40mg/m2 Methotrexate. The maintenance dose for ALL is 15‐30mg/m2 once or twice weekly.
Other examples:
 3.3mg/m2 in combination with other cytostatic agent once daily for 4‐6 week.
 2.5mg/kg every week.
 High dose regimen between 1 to 12 g/m2 (i.v. 1‐6 h) repeated every 1‐3 weeks.
 20mg/m2 in combination with other cytostatic agents once week.

Breast cancer
Cyclic combination with Cyclophosphamide, Methotrexate and Fluorouracil has been used as
adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph
nodes. The dose of Methotrexate is 40mg/m2 intravenously on the first and eighth days of the cycle.
The treatment is repeated at 3 week intervals. Methotrexate, in intravenous doses of 10‐60mg/m2,
could be included in cyclic combination regimes with other cytotoxic drugs in the treatment of
advanced breast cancer.
Osteosarcoma
Effective adjuvant chemotherapy requires the administration of several cytotoxic chemotherapeutic
drugs. In addition to high dose Methotrexate with Calcium Folinate Rescue, Doxorubicin, Cisplatin
and a combination of Bleomycin, Cyclophosphamide and Dactinomycin (BCD) can be given.
Methotrexate is used in high doses (8,000‐12,000 mg/m2) once weekly. If dose is insufficient to reach
real serum concentration of 10‐3 mol/L at the end of infusion, dose can be increased to 15g/m2 for
subsequent treatment. Calcium Folinate Rescue is necessary. Methotrexate has also been used as
the sole treatment in metastatic cases of osteosarcoma.
Older people
Dose reduction should be considered in elderly patient due to reduced liver and kidney function as
well as lower folate reserves which occur with increased age.
Patient with impaired renal function
Methotrexate should be used with caution in patients having impaired renal function. The dose
regimens must be adjusted according to the creatinine clearance and serum Methotrexate
concentrations.
 If creatinine clearance (ml/min) is >50, 100% MTX dose can be given
 If creatinine clearance (ml/min) is 20‐50, 50% of MTX dose can be given
 If creatinine clearance (ml/min) is <20, MTX should not be given
Patients with impaired hepatic function
Methotrexate should be administered with great caution, if at all, to patients with significant current
or previous liver disease, especially when caused by alcohol. Methotrexate is contraindicated if
bilirubin values are >5 mg/dl (85.5 μmol/L).
Paediatric population
Methotrexate should be used with caution in paediatric patients. Treatment should follow currently
published therapy protocols for children (see Section 4.4).

 

Mexat is contraindicated in patients who have  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Sever liver impairment (See Section 4.2).  Alcohol abuse.  Severe renal impairment (Creatinine clearance less than 20 ml/min, see section 4.2).  Pre‐existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia.  Serious, acute or chronic infections such as tuberculosis and HIV.  Ulcers of the oral cavity and known active gastrointestinal ulcer disease.  Pregnancy, breast‐feeding (see section 4.6).  Concurrent vaccination with live vaccines.

Fatal toxicity in association with intravenous and intrathecal administration due to dose
miscalculation has been reported. Particular caution should be exercised when calculating the dose
( see 4.2. posology and administration).
Because of the risk of severe toxic reactions (which can be fatal), Methotrexate must only be used in
life‐threatening neoplastic diseases. Deaths have been reported during treatment of malignancies
with Methotrexate. The doctor should inform the patient of the risks of treatment and the patient
should be monitored constantly by the doctor.
Fertility
Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual
dysfunction and amenorrhoea in humans during and for a short period after the discontinuation of
treatment, affecting spermatogenesis and oogenesis during the period of its administration ‐ effects
that appear to be reversible on discontinuing therapy.
Teratogenicity – Reproductive risk
Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. Therefore, the
possible effects on reproduction, pregnancy loss and congenital malformations should be discussed
with female patients of childbearing age (see Section 4.6). In non‐oncologic indications, the absence
of pregnancy must be confirmed before Mexat is used. If women of a sexually mature age are
treated, effective contraception must be used during treatment and for at least six months after.
For contraception advice for men see Section 4.6.

Tumor lysis syndrome
Like other cytotoxic agents, Methotrexate can induce tumour lysis syndrome in patients with rapidly
growing tumours. Appropriate supportive treatment and pharmacological measures can prevent or
alleviate such complications.
Methotrexate and NSAIDs
Unexpected severe (including fatal) myelosuppression, aplastic anaemia and gastrointestinal toxicity
have been reported in connection with concomitant treatment with Methotrexate (usually at a high
dose) and non‐steroidal anti‐inflammatory agents (NSAIDs) (See 4.5 interaction with other medicinal
products and other forms of interaction).
Concomitant Methotrexate treatment and radiotherapy can increase the risk of soft tissue necrosis
and osteonecrosis.
Intrathecal and intravenous administration of Methotrexate can result in acute encephalitis and
acute encephalopathy, possibly with a fatal outcome. Patients with periventricular CNS lymphoma
who are given Methotrexate intrathecally have reportedly developed cerebral herniation.
Methotrexate and pleural effusion/ascites
Methotrexate is eliminated slowly from collections of fluid (e.g. pleural effusion, ascites). This results
in a prolonged terminal half‐life and unexpected toxicity. In patients with significant collections of
fluid, drainage of the fluid before treatment is started and monitoring of plasma Methotrexate levels
are recommended.
If stomatitis, diarrhoea, haematemesis or black stool occurs, therapy with Methotrexate should be
discontinued due to the danger of haemorrhagic enteritis or death from intestinal perforation or
dehydration (see Section 4.8 undesirable side effects).

Conditions in which there is folic acid deficiency can increase the risk of Methotrexate toxicity.
In association with intrathecal administration or in high dose treatment, Methotrexate must not be
mixed with solutions which contain preservatives (see also 6.6).
Solutions of Methotrexate which contain the preservative benzyl alcohol are not recommended for
use in infants. Gasping syndrome with fatal outcome has been reported in infants following
intravenous treatment with solutions containing the preservative benzyl alcohol. Symptoms include
rapid onset of respiratory problems, hypotension, bradycardia and cardiovascular collapse.
Infection or immunological conditions
Methotrexate must be used with great care in connection with active infection and is usually
contraindicated in patients with manifest suppression of the immune response or where
immunodeficiency is demonstrated by laboratory tests.
Pneumonia (which in certain cases can lead to respiratory failure) can occur. Potentially fatal
opportunistic infections including Pneumocystis carinii pneumonia can occur in association with
methotrexate treatment. When a patient exhibits pulmonary symptoms, the possibility of
Pneumocystis carinii pneumonia should be considered (see Section 4.8).
Immunisation
Methotrexate may interfere with results of immunological tests. Immunisation after a vaccination
may be less effective in association with Methotrexate treatment.Particularly caution should be
exercised in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B
or C) due to possible activation. Immunisation with live viruses is not normally recommended.
Skin toxicity: Due to the risk of phototoxicity, the patient must avoid sunlight and solarium.
Monitoring treatment
Patients on Methotrexate treatment must be closely monitored so that toxic effects can be detected
immediately. Analyses before treatment must include a full blood count with differential and platelet
counts, liver enzymes, testing for hepatitis B and C infections, renal function test and x‐ray of the
lungs. Toxic effects of Methotrexate can occur even with low doses and therefore it is important to
monitor treated patients carefully. Most undesirable effects are reversible if detected early.
After initiation of treatment or when there is a change in the dose, or during periods in which there is
an increased risk of elevated levels of Methotrexate (e.g. in dehydration), monitoring should be
performed.
Bone marrow biopsy must be performed as necessary.
Serum Methotrexate level monitoring can significantly reduce Methotrexate toxicity and routine
monitoring of serum Methotrexate level is necessary depending on dosage or therapy protocol.
Leucopenia and thrombocytopenia occur usually 4 ‐14 days after administration of Methotrexate. In
rare cases recurrence of leucopenia may occur 12 ‐ 21 days after administration of Methotrexate.
Methotrexate therapy should only be continued if the benefit outweighs the risk of severe
myelosuppression (see Section 4.2).

Haematopoietic suppression: Haematopoietic suppression induced by Methotrexate may occur
abruptly and at apparently safe doses. In the event of any significant drop in leukocytes or platelets,
treatment must be discontinued immediately and appropriate supportive therapy instituted. Patients
must be instructed to report all signs and symptoms suggestive of infection. In patients
concomitantly taking haematotoxic medications (e.g. Leflunomide), the blood count and platelets
should be closely monitored.

Liver function tests: Particular attention should be paid to the onset of liver toxicity. Treatment
should not be initiated or should be discontinued if there are any abnormalities in liver function tests
or liver biopsies, or if these develop during therapy. Such abnormalities should return to normal
within two weeks; after which, treatment may be resumed at the discretion of the doctor. Further
research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen
can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without
any risk factors and patients with risk factors, e.g. excessive prior alcohol consumption, persistent
elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders,
diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged
Methotrexate treatment or cumulative doses of 1.5 g or more.
Screening for liver‐related enzymes in serum: A transient rise in transaminase levels to twice or three
times the upper limit of normal has been reported with a frequency of 13 ‐ 20%. In the event of a
constant increase in liver related enzymes, consideration should be given to reducing the dose or
discontinuing therapy.

Insulin‐dependent diabetes
Patients suffering from insulin‐dependent diabetes should be carefully monitored because liver
cirrhosis and an increase in transaminase can occur.
Due to the potentially toxic effect on the liver, additional hepatotoxic medications should not be
given during treatment with Methotrexate unless clearly necessary and alcohol consumption should
be avoided or greatly reduced (see Section 4.5). Closer monitoring of liver enzymes should be
undertaken in patients concomitantly taking other hepatotoxic medications (e.g. Leflunomide). The
same should also be taken into consideration if haematotoxic medications are co‐administered.
Malignant lymphomas may occur in patients receiving low‐dose Methotrexate; in which case,
Methotrexate must be discontinued. If lymphomas should fail to regress spontaneously, initiation of
cytotoxic therapy is required.
Renal function: Methotrexate treatment in patients with impaired renal function should be
monitored via renal function tests and urinalysis, since impaired renal function reduces the
elimination of Methotrexate, which may result in severe adverse reactions.

In cases of possible renal impairment (e.g. in elderly patients), close monitoring of renal function is
required. This is particularly applies to the co‐administration of medicinal products which affect
Methotrexate excretion cause kidney damage (e.g. non‐steroidal anti‐inflammatory drugs) or which
can potentially lead to haematopoietic disorder. Dehydration may also potentiate the toxicity of
Methotrexate. Alkalinization of the urine and increase a high diuresis is recommended.
Respiratory System: Acute or chronic interstitial pneumonitis, often associated with blood
eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea,
cough (especially a dry non‐productive cough) and fever for which patients should be monitored at
each follow‐up visit. Patients should be informed of the risk of pneumonitis and advised to contact
their doctor immediately should they develop persistent cough or dyspnoea.
In addition, pulmonary alveolar haemorrhage has been reported with Methotrexate used in
rheumatologic and related indications. This event may also be associated with vasculitis and other
comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is
suspected to confirm the diagnosis.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough
investigation (including chest X‐ray) 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.
Pulmonary symptoms require a quick diagnosis and discontinuation of Methotrexate therapy.
Pneumonitis can occur at all doses.
Vitamin preparations or other products containing Folic Acid, Folinic Acid or their derivatives may
decrease the effectiveness of Methotrexate.
Children
Methotrexate should be used with caution in paediatric patients. Treatment should follow currently
published therapy protocols for children. 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 (1g/m2). Symptomatic patients were commonly noted to have leukoencephalopathy
and/or microangiopathic calcifications on diagnostic imaging studies.
Elderly
Because of deterioration in liver and kidney function as well as reduced folic acid reserves, relatively
low doses should be considered in elderly patients. These patients must be closely monitored for
early signs of toxicity.
Sodium
Methotrexate injection contains 345.59mg (15.033 mmol) of sodium per maximum daily dose
(1800mg). This should be taken into consideration by patients on a controlled sodium diet.

Ciprofloxacin
Excretion of Methotrexate possibly reduced (increased risk of toxicity).
Non‐steroidal anti‐inflammatory drugs (NSAIDs).
NSAID preparations must not be given prior to or concomitantly with the high doses of Methotrexate
used in the treatment of conditions such as osteosarcoma. Concomitant administration of NSAIDs
and Methotrexate at high doses has reportedly elevated and prolonged serum Methotrexate levels,
resulting in deaths from severe haematological and gastrointestinal toxicity. NSAID preparations and
salicylates have reportedly reduced the tubular secretion of Methotrexate in animal models and may
increase its toxicity by increasing Methotrexate levels. Concomitant treatment with NSAIDs and low
doses of Methotrexate must therefore be administered with caution.
Nitrous oxide
The use of nitrous oxide potentiates the effect of Methotrexate on folate metabolism, yielding
increased toxicity such as severe, unpredictable myelosuppression, stomatitis and neurotoxicity with
intrathecal administration. Whilst this effect can be reduced by administering Calcium Folinate, the
concomitant use should be avoided.
Leflunomide
Methotrexate in combination with Leflunomide can increase the risk of pancytopenia.
Probenecid
Renal tubular transport is diminished by Probenecid, and its use together with Methotrexate must be
avoided.

Penicillins
Penicillins can reduce renal clearance of Methotrexate. Haematological and gastrointestinal toxicity
have been observed in combination with high and low dose Methotrexate.
Oral antibiotics
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 hence the metabolism of Methotrexate by bacteria. In
isolated cases, Trimethoprim/Sulfamethoxazole has reportedly increased myelosuppression in
patients treated with Methotrexate, probably due to reduced tubular secretion and/or an additive
antifolate effect.
Chemotherapeutic products
An increase in renal toxicity can be observed when high doses of Methotrexate are given in
combination with potentially nephrotoxic chemotherapeutic agents (e.g. Cisplatin).
Radiotherapy
Concurrent Methotrexate and radiotherapy can increase the risk of soft tissue necrosis and
osteonecrosis.
Cytarabine
Concomitant therapy with Cytarabine and Methotrexate can increase the risk of severe neurological
side effects ranging from headache to paralysis, coma and stroke‐like episodes.
Hepatotoxic products
The risk of increased hepatotoxicity when Methotrexate is administered concurrently with other
heptatotoxic products has not been studied. Hepatotoxicity has however been reported in such
cases. Patients receiving concomitant treatment with drugs with a known hepatotoxic effect (e.g.
Leflunomide, Azathioprine, Sulfasalazine, Retinoids) must be carefully monitored for signs of any
increase in hepatotoxicity.
Theophylline
Methotrexate can reduce clearance of Theophylline. Theophylline levels must therefore be
monitored during concomitant treatment with Methotrexate.
Mercaptopurine
Methotrexate increases plasma content of Mercaptopurine. The combination of Methotrexate and
Mercaptopurine can therefore require dose adjustment.
Drugs with high plasma protein binding
Methotrexate is partially bound to serum albumin. Other highly bound drugs such as Salicylates,
Phenylbutazone, Phenytoin and Sulfonamides can increase the toxicity of Methotrexate by means of
displacement.
Furosemide
Concomitant administration of Furosemide and Methotrexate can result in increased levels of
Methotrexate due to competitive inhibition of tubular secretion.

Vitamins
Vitamin preparations containing Folic Acid or its derivatives can cause a reduced response to
systemically administered Methotrexate, however conditions in which there is a deficiency of Folic
Acid can increase the risk of Methotrexate toxicity.
9
Proton Pump Inhibitors
Literature data indicate that co‐administration of proton pump inhibitors and Methotrexate,
especially at high dose, may result in elevated and prolonged plasma levels of Methotrexate and/or
its metabolite, possibly leading to Methotrexate toxicity.

Women of childbearing potential/Contraception in females
Women must not get pregnant during Methotrexate therapy, and effective contraception must be
used during treatment with Methotrexate and at least 6 months thereafter (see Section 4.4). Prior to
initiating therapy, women of childbearing potential must be informed of the risk of malformations
associated with Methotrexate and any existing pregnancy must be excluded with certainty by taking
appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated
as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential
must be counselled regarding pregnancy prevention and planning.
Contraception in males
It is not known if Methotrexate is present in semen. Methotrexate has been shown to be genotoxic
in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be
excluded. Limited clinical evidence does not indicate an increased risk of malformations or
miscarriage following paternal exposure to low‐dose Methotrexate (less than 30mg/week). For
higher doses, there is insufficient data to estimate the risks of malformations or miscarriage
following paternal exposure.
As precautionary measures, sexually active male patients or their female partners are recommended
to use reliable contraception during treatment of the male patient and for at least 6 months after
cessation of Methotrexate. Men should not donate semen during therapy or for 6 months following
discontinuation of Methotrexate.
Pregnancy
Methotrexate is contraindicated during pregnancy in non‐oncological indications (see Section 4.3). If
pregnancy occurs during treatment with Methotrexate and up to six months thereafter, medical
advice should be given regarding the risk of harmful effects on the child associated with treatment
and ultrasonography examinations should be performed to confirm normal foetal development. In
animal studies, Methotrexate has shown reproductive toxicity, especially during the first trimester
(see Section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported
to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular,
central nervous system and extremity‐related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions,
intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.
• Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low‐dose
Methotrexate treatment (less than 30mg/week), compared to a reported rate of 22.5% in diseasematched
patients treated with drugs other than Methotrexate.
• Major birth defects occurred in 6.6% of live births in women exposed to low‐dose Methotrexate
treatment (less than 30mg/week) during pregnancy, compared to approximately 4% of live births in
in disease‐matched patients treated with drugs other than Methotrexate.
Insufficient data is available for Methotrexate exposure during pregnancy higher than 30mg/week,
but higher rates of spontaneous abortions and congenital malformations are expected, in particular
at doses commonly used in oncologic indications
When Methotrexate was discontinued prior to conception, normal pregnancies have been reported.

When used in oncological indications, Methotrexate should not be administered during pregnancy in
particular during the first trimester of pregnancy. In each individual case the benefit of treatment
must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if
the patient becomes pregnant while taking Methotrexate, the patient should be informed of the
potential risk to the foetus.
Breastfeeding
Methotrexate passes into breast milk in quantities such that there is a risk to the child even at
therapeutic doses. Breast feeding must therefore be discontinued during treatment with
Methotrexate.
Fertility
Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans,
Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea.
These effects appear to be reversible after discontinuation of therapy in most cases. In oncologic
indications, women who are planning to become pregnant are advised to consult a genetic
counselling centre, if possible, prior to therapy and men should seek advice about the possibility of
sperm preservation before starting therapy as Methotrexate can be genotoxic at higher doses
(see Section 4.4).

Since fatigue and dizziness can occur as an undesirable effect, ability to react and judgement can be
impaired, which should be taken into account for example when driving or carrying out work
involving a high degree of precision.

Conventional and high dose therapy
The frequency and degree of severity of undesirable effects depends on the dose administered, the
duration of exposure and method of administration, but side effects have been seen at all doses and
can occur at any time during treatment. Most undesirable effects are reversible when detected at an
early stage. When severe reactions occur, the dose should be reduced or treatment discontinued and
appropriate measures initiated (See 4.9). If treatment with Methotrexate is resumed, this should be
done with caution after adequate consideration of the further need for the drug. Increased vigilance
with regard to any recurrence of toxicity is required.
The most frequently reported undesirable effects include ulcerative stomatitis, leukopenia, nausea
and bloating. Other frequently reported undesirable effects are feeling unwell, unusual tiredness,
chills and fever, dizziness, reduced resistance to infections. Treatment with Folinic acid during high
dose therapy can counteract or alleviate a number of undesirable effects. Temporary discontinuation
of therapy is recommended if there are signs of leukopenia.

The following undesirable effects have also been reported, but their frequency has not been
established: Pneumocystis carinii pneumonia, (including reversible cases), foetal death, damage to
the foetus, abortion.
Systemic organ toxicity
Lymphoma
Malignant lymphoma which can go into remission after discontinuation of the treatment with
Methotrexate can occur in patients on low dose therapy, and may not therefore require any
cytotoxic treatment. Methotrexate should be discontinued first and appropriate treatment initiated
if the lymphoma does not regress.
Haematological
Methotrexate can suppress haematopoiesis and cause anaemia, aplastic anaemia, pancytopenia,
leukopenia, neutropenia and/or thrombocytopenia. Methotrexate must be administered with
caution to patients with malignancies and underlying factors affecting haematopoiesis. When
treating neoplastic conditions, treatment with Methotrexate should only be given provided the
potential benefits outweigh the risk of myelosuppression.

Lungs
Lung disease caused by Methotrexate, including acute or chronic interstitial pneumonitis, is a
potentially dangerous complication, which can occur at any time during the course of treatment. This
undesirable effect has been reported at low doses and is not always totally reversible. Deaths have
been reported. Signs of pulmonary involvement or symptoms such as dry non‐productive cough,
fever, chest pains, dyspnoea, hypoxemia and infiltrate on X‐ray of the lungs, or non‐specific
pneumonitis which occurs in connection with Methotrexate therapy, may indicate potentially serious
damage and requires discontinuation of treatment and careful investigation. Lung changes can occur
at all doses. The possibility of infection (including pneumonia) must be excluded.
Gastrointestinal
If vomiting, diarrhoea or stomatitis occur, with resulting dehydration, Methotrexate therapy must be
discontinued until the patient has recovered. Haemorrhagic enteritis and deaths caused by intestinal
perforation can occur. Methotrexate must be used with great caution in patients with peptic ulcers
or ulcerative colitis. Stomatitis can be prevented or alleviated by Folinic Acid mouthwashes.
Liver
Methotrexate involves a potential risk of acute hepatitis and chronic (fibrosis and cirrhosis)
hepatotoxicity. Chronic toxicity is potentially fatal and occurs commonly after long‐term use (in
general after 2 years or more) and after a total cumulative dose greater than 1.5g. In studies of
psoriasis patients hepatotoxicity was seen to be proportional to the cumulative dose and was
potentiated by alcoholism, overweight, diabetes and age.
Transient deterioration in liver enzyme values is frequently seen after Methotrexate treatment and
does not usually necessitate adjustment of treatment. Existing abnormal liver values and/or
reduction in serum albumin can indicate severe hepatotoxicity.
Methotrexate has caused reactivation of hepatitis B infections and exacerbation of hepatitis C
infections, in some cases with fatal outcome. Some cases of hepatitis B reactivation have occurred
following discontinuation of Methotrexate. Clinical and laboratory tests should be performed to
investigate any occurrence of liver disease in patients with prior hepatitis B or C infections. Based on
these investigations, treatment with Methotrexate may prove unsuitable for certain patients.
In the event of impaired liver function, the undesirable effects of Methotrexate (in particular
stomatitis) can be exacerbated.

Kidneys
Methotrexate can cause kidney damage which can result in acute renal failure. Renal function can be
exacerbated following high dose therapy to such an extent that the excretion of Methotrexate is
inhibited, as a result of which systemic Methotrexate toxicity can occur. In order to prevent renal
failure, alkalinization of the urine and adequate fluid intake (at least 3 l/day) are recommended.
Measurement of serum Methotrexate and renal function is recommended.
Skin
Serious, in some cases fatal skin reactions, including toxic epidermal necrolysis (Lyell’s syndrome),
Stevens‐Johnson syndrome and erythema multiforme have been reported within a few days of oral,
intramuscular, intravenous or intrathecal treatment with Methotrexate in single or repeat doses.
Radiation dermatitis and sunburn can be accentuated after use of Methotrexate.
CNS
There are reports of leukoencephalopathy after intravenous treatment with Methotrexate in
patients who have undergone craniospinal radiotherapy. Severe neurotoxicity, often manifested as
generalised or focal seizures have been reported with an unexpected increase in frequency in
children with acute lymphoblastic leukaemia treated with a moderately high dose of intravenous
methotrexate (1 g/m2). Symptomatic patients frequently had leukoencephalopathy and/or
microangiopathic calcifications in X‐ray investigations.

Chronic leukoencephalopathy has also been reported in patients treated with repeated high doses of
Methotrexate together with Folinic Acid, even without concomitant cranial radiotherapy.
Discontinuation of the Methotrexate therapy did not always result in full recovery.
Leukoencephalopathy has also been reported in patients treated with Methotrexate tablets.
One transient acute neurological syndrome has been observed in patients undergoing high dose
therapy. Manifestations of this neurological syndrome can include abnormal behaviour, focal
sensorimotor symptoms including transient blindness, and abnormal reflexes. The exact cause is
unclear.
Cases of neurological side effects ranging from headache to paralysis, coma and stroke‐like episodes
have been reported, primarily in children and adolescents receiving concomitant medication with
Cytarabine.
Intrathecal therapy
The subacute neurotoxicity is usually reversible after discontinuing Methotrexate.

Chemical arachnoiditis, which can occur a few hours after intrathecal administration of Methotrexate
is characterised by headache, back pain, stiff neck, vomiting, fever, meningism and pleocytosis in the
cerebrospinal fluid similar to that in bacterial meningitis. Arachnoiditis generally disappears within a
few days.
Subacute neurotoxicity, common after frequently repeated intrathecal administration, mainly affects
the motor functions in the brain or spinal cord. Paraparesis/paraplegia, with involvement of one or
more spinal nerve roots, tetraplegia, cerebellar dysfunction, cranial nerve paralysis and epileptic
seizures can occur.
Necrotising demyelinating leukoencephalopathy can occur several months or years after starting
intrathecal therapy. The condition is characterized by progressive neurological deterioration with
insidious onset, confusion, irritability and somnolence. Ultimately severe dementia, dysarthria,
ataxia, spasticity, seizures and coma can occur. The condition can be fatal. Leukoencephalopathy
occurs primarily in patients who have received large quantities of intrathecal Methotrexate in
combination with cranial radiotherapy and/or systemically administered Methotrexate.
Signs of neurotoxicity (meningeal inflammation, transient or permanent paresis, encephalopathy)
must be followed up after intrathecal administration of Methotrexate.

Reporting of suspected adverse reactions
To report any side effect(s) in Saudi Arabia, please contact:
The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966‐11‐205‐7662
• SFDA call center 19999
• Toll free phone: 8002490000
• E‐mail: npc.drug@sfda.gov.sa
 Website: www.sfda.gov.sa/npc

Experience of overdose with the product has in general been associated with oral and intrathecal
treatment, although overdose in association with intravenous and intramuscular administration has
also been reported.
Reports of oral overdose have often been due to accidental daily instead of weekly ingestion.
Commonly reported symptoms following oral overdose include the symptoms and signs seen at
pharmacological doses, in particular haematological and gastrointestinal reactions such as
leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis,
stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In
certain cases no symptoms were reported. There are reports of deaths associated with overdose. In
these cases there were also reports of conditions involving sepsis or septic shock, renal failure and
aplastic anaemia.
The most common symptoms of intrathecal overdose are CNS symptoms including headache, nausea
and vomiting, seizures or convulsions and acute toxic encephalopathy. In certain cases, no symptoms
were reported. There have been reports of deaths following intrathecal overdose. In these cases
there were also reports of cerebellar herniation accompanying elevated intracranial pressure and
toxic encephalopathy.

Recommended treatment
Antidote therapy: Folinic acid should be given parenterally at a dose at least the size of the
Methotrexate dose and should wherever possible be administered within an hour. Folinic Acid is
indicated to minimize toxicity and counter the effect of Methotrexate overdose. Folinic Acid
treatment should be initiated as soon as possible. The longer the interval between the administration
of Methotrexate and the initiation of Folinic Acid, the less the effect of Folinic Acid in suppressing the
toxic effect. Monitoring of serum Methotrexate concentrations is necessary to be able to determine
the optimum dose of Folinic Acid and the length of the treatment.
In the event of a major overdose, hydration and alkalinization of the urine may be required to
prevent precipitation of Methotrexate and/or its metabolites in the renal tubules. Neither standard
haemodialysis nor peritoneal dialysis have been shown to increase the elimination of Methotrexate.
Acute intermittent haemodialysis with the use of highly permeable dialyser may be attempted for
Methotrexate intoxication.
Intrathecal overdose may require intensive systemic supportive measures such as systemic
administration of high doses of Folinic Acid, alkaline diuresis, acute CSF drainage and ventricular
lumbar perfusion.

Pharmacotherapeutic group: Cytostatic agent: Folic Acid analogue
ATC code: L01BA01
Methotrexate is a Folic Acid antagonist with a cytostatic effect. Methotrexate inhibits the conversion
of folic acid to Tetrahydrofolic Acid since the compound has a greater affinity for the enzyme
Dihydrofolate reductase than the natural substrate folic acid. As a result, DNA synthesis and new cell
formation are inhibited. Methotrexate is s‐phase specific. Actively proliferating tissues such as
malignant cells, bone marrow, foetal cells, epithelium and buccal and intestinal mucosa are generally
most susceptible to Methotrexate.

Following intravenous administration, peak serum concentrations of Methotrexate are reached after
approx. 0.5 – 1 hour. There is wide inter‐individual and intra‐individual variation, especially with
repeated doses. Saturation of oral absorption occurs at doses above 30mg/m2. About half of the
absorbed Methotrexate is bound to plasma proteins, but binding is reversible, and Methotrexate is
easily diffused into the cells, with the highest concentrations reached in the liver, spleen and kidneys
in the form of polyglutamate can be found which can be retained for few weeks or months.
Methotrexate also passes to a lesser degree into cerebrospinal fluid. The half‐life is approx. 3 to 10
hours with low dose therapy and approx. 8 to 15 hours with high dose therapy. Elimination from
plasma is triphasic and the majority of the Methotrexate is excreted unchanged in urine within 24
hours.

Animal studies show that Methotrexate impairs fertility and that it is embryotoxic, foetotoxic and
teratogenic. Methotrexate is mutagenic in vivo and in vitro, but the clinical significance is unknown
since rodent carcinogenicity studies have produced differing results. Chronic toxicity studies in mice,
rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and
hepatotoxicity.

Sodium chloride
Sodium hydroxide (For pH adjustment)
Hydrochloric acid (For pH adjustment)
Water for injection

Owing to the absence of compatibility studies, this medicine should not be mixed with other
medicines except those mentioned in section 6.6.

Shelf life of unopened vial: 24 months.

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date which is stated on the pack. The expiry date refers to
the last day of that month.
Do not store above 25°C.
Keep the vial in the outer carton in order to protect from light.
Do not use this medicine if you notice that the solution is not clear or contains particles.
For storage conditions of the diluted medicinal product, see Section 6.3.
For single‐use only. Any unused solution should be discarded.

Mexat 25mg/ml solution for injection is filled in Type‐I glass vial sealed with rubber stopper and
aluminium flip‐off cap.
Pack sizes:
1×2ml vial (50mg/2ml)
1×20ml vial (500mg/20ml), 10×20ml vial (500mg/20ml)
1×40ml vial (1000mg/40ml), 10×40ml vial (1000mg/40ml)

Not all pack sizes may be marketed.

The solution should be visually inspected prior to use. Only clear solution practically free from
particles should be used.
Mexat may be further diluted with an appropriate preservative‐free medium such as Glucose
Solution (5%) or Sodium Chloride Solution (0.9%).
With respect to the handling the following general recommendations should be considered: The
product should be used and administered only by trained personnel; the mixing of the solution
should take place in designated areas, designed to protect personnel and the environment (e.g safety
cabins); protective clothing should be worn (including gloves, eye protection, and masks if
necessary).
Pregnant healthcare personnel should not handle and/or administer Metotrexat.

Methotrexate should not come into contact with the skin or mucosa. In the event of contamination,
the affected area must be irrigated immediately with copious quantities of water at least ten
minutes.
For single‐use only. Any unused solution should be discarded. Waste should be disposed of carefully
in suitable separate containers, clearly labelled as to their contents (as the patient's body fluids and
excreta may also contain appreciable amounts of antineoplastic agents and it has been suggested
that they, and material such as bed linen contaminated with them, should also be treated as
hazardous waste). Any unused product or waste should be disposed of in accordance with local
requirements by incineration.
Adequate procedures should be in place for accidental contamination due to spillage; staff exposure
to antineoplastic agents should be recorded and monitored.