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Active substance(s): METHOTREXATE DISODIUM

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Methotrexate for the treatment of psoriasis and rheumatoid arthritis should only
be administered 1x/week. Methotrexate administered for the treatment of
oncological diseases should be administered cautiously taking into account the
body surface area.
Incorrect dosing of methotrexate can result in serious potentially fatal adverse
drug reactions. Health care professionals and the patients should be advised


Methotrexate 2mg/ml Oral Solution


Each ml of oral solution contains 2.19mg Methotrexate disodium equivalent to 2mg
Excipients with known effect
Sodium Methyl Parahydroxybenzoate
Sodium Ethyl Parahydroxybenzoate
Sulphites (from the flavour)
For the full list of excipients, see section 6.1.


A clear yellow oral solution.




Therapeutic indications
Methotrexate 2mg/ml Oral Solution is indicated in the following oncological

The maintenance treatment of Acute Lymphocytic Leukaemia (ALL) in children
and adults.

The treatment of malignant trophoblastic tumours

Methotrexate 2mg/ml Oral Solution is indicated in:


The treatment of severe active rheumatoid arthritis in adults.

The treatment of severe forms of psoriasis vulgaris including chronic plaque
psoriasis, erythrodermic psoriasis, psoriatic arthritis and pustular psoriasis which
are not responsive to other conventional therapies such as phototherapy, PUVA
and retinoids.

Posology and method of administration
Treatment with ‘Methotrexate 2 mg/ml oral should be initiated and supervised by
physicians with experience in antimetabolite chemotherapy and the management of
the approved indications. The treatment regimen should be decided on an individual
patient basis, with reference to current treatment protocols.
During treatment with methotrexate patients require careful monitoring to avoid
severe toxicities and to ensure fast identification of toxic side effects. Measurement of
serum methotrexate level is absolutely essential.
Pharmaceutical forms with lowest possible strength should be used. Fatal cases of
intoxication have been reported after intravenous and intrathecal administration of
incorrect calculated doses. Therefore, dosage must be carefully calculated in all
The application and dosage recommendation for the administration of methotrexate
for different indications varies considerably. Some common dosages and therapy
protocols, which have proved to be efficacious in the therapy of the disorder in each
case, are given below. Current published protocols should be always consulted for the
dosages and the method and sequence of administration.
Doses in excess of 100 mg are usually given by intravenous infusion.
Skin and mucus membrane contact with methotrexate should be avoided. If
methotrexate contaminates the skin it should be washed off immediately using
copious amounts of running water for at least ten minutes.

Dosage for Rheumatoid arthritis

IMPORTANT: For rheumatic conditions, this medicine should be taken once a week.
Incorrect dosing may lead to serious adverse effects including fatalities.
The prescriber may specify the day of intake on the prescription.
The usual dose is 7.5 – 15 mg (3.75 ml – 7.5 ml) once weekly. The planned weekly
dose may be administered in three divided doses over 36 hours however, this is a
secondary choice (in case of intolerance) and the once weekly regimen should always
be started first.. The schedule may be adjusted gradually, depending on the individual
activity of the disease and tolerability by the patient to achieve an optimal response
but should not exceed a total weekly dose of 20 mg (10 ml). Thereafter the dose
should be reduced to the lowest possible effective dose which in most cases is
achieved within 6 weeks.
The treating physician will decide how long the patient should be treated. Treatment
of severe active rheumatoid arthritis represents a longer-term treatment.
Dosage in oncological indications (low dose therapy: single dose < 100 mg/m²)
Doses are usually based on the patient’s body surface area (BSA).
Doses in excess of 100 mg are usually given parenterally, when an injectable
preparation should be used.
A test dose of 5 - 10 mg parenterally is recommended, one week prior to therapy to
detect idiosyncratic adverse events.
Malignant Trophoblastic Tumours:
15mg/m2, Day 1 to Day 5. Usually such courses may be repeated 3 to 5 times as
required, with rest periods of one or more weeks interposed between courses, until
any manifesting toxic symptoms subside.
Acute Lymphocytic Leukaemia
Low-dose methotrexate is used in the maintenance treatment of acute lymphocytic
leukaemia in children and adults within complex protocols in combination with other
cytostatic medicinal products for maintenance treatment.
Common accepted single doses lie in the range of 20- 40mg/m2 body surface area.
If methotrexate is administered in combination chemotherapy regimens, the dosage
should be reduced, taking into consideration any overlapping toxicity of the other
drug components.
Dosage for psoriasis:

Before starting treatment it is advisable to give the patient a test dose of 2.5 – 5.0 mg
to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests
are normal, treatment may be initiated. The usual dose is 10mg – 25mg (5ml –
12.5ml) taken once weekly. The planned weekly dose can be administered as three
divided doses over 24 hours. As necessary, the total weekly dose can be increased up
to 25mg. Thereafter the dose should be reduced to the lowest effective dose according
to therapeutic response which is most cases is achieved within 4 to 8 weeks.
The treating physician will decide how long the patient should be treated. Treatment
of psoriasis and psoriatic arthritis represents a longer-term treatment.
The patient should be fully informed of the risks involved and the clinician should
pay particular attention to the appearance of liver toxicity by carrying out liver
function tests before starting methotrexate treatment, and repeating these at 2 to 4
month intervals during therapy (see section 4.4). The aim of therapy should be to
reduce the dose to the lowest possible level with the longest rest period. The use of
methotrexate may permit the return to conventional topical therapy which should be

Special Populations
Methotrexate should be used with extreme caution in elderly patients, a reduction in
dosage should be considered due to reduced liver and kidney function as well as
lower folate reserves which occurs with increased age.
Patients with renal impairment
Since methotrexate is predominantly eliminated renally, in patients with impaired
creatinine clearance, delayed elimination is to be expected, which can lead to severe
side effects. In patients with impaired renal function, the dose regimens must be
adjusted according to the creatinine clearance and serum methotrexate concentrations.
Renal function can be adversely affected by the application of methotrexate.
Methotrexate should be used with caution in patients with impaired renal function.
The following dose adjustments have been used in oncological indications. Reference
should be made to current published treatment protocols.

Creatinine-Clearance (ml/min)
> 80
< 60

% of standard dose
Alternative therapy should be

The following dose adjustments apply to patients with renal impairment with the
indication of psoriasis / psoriatic arthritis and the indication of rheumatoid arthritis.

Creatinine-Clearance (ml/min)
> 50
< 20

% of standard dose
Alternative therapy should be

Paediatric population
Oncological indication
Methotrexate should be used with caution in children. Standard therapy protocols
should be consulted for dosages and method and sequence of administration. Fatal
cases of intoxication have been reported after intravenous and intrathecal
administration of incorrect calculated doses. Therefore, dosage must be carefully
calculated in children.
Non-oncological indications
Safety and effectiveness in children and adolescents have not been established, other
than in cancer therapy. Therefore, the use of Methotrexate 2mg/ml Oral Solution is
not recommended

Method of administration
The medicine is for oral administration only.
The medicine should be administered using the syringe provided in the pack or as
directed by the healthcare professional. (See Section 6.6)
Methotrexate can be taken with or without food.
Once the dose has been swallowed, a glass of water should be drunk to remove any
methotrexate residue from the oral cavity.


Methotrexate is contra-indicated in the following:

Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1

severe/significant renal impairment (see section 4.2)

significant hepatic impairment


active infectious disease

overt or laboratory evidence of immunodeficiency syndrome(s)

pre-existing blood dyscrasias, such as bone marrow hypoplasia, leucopenia, or
thrombocytopenia or serious anaemia

stomatitis, gastrointestinal ulceration

lactation (see section 4.6)

during methotrexate therapy concurrent vaccination with live vaccines must not
be carried out.
Additionally for non-oncological indications:


Pregnancy (see section 4.6)

Special warnings and precautions for use
Warnings regarding non-oncological indications
• The prescriber may specify the day of intake on the prescription in order
to avoid any confusion likely to result in accidental overdose.
• Patients should be aware of importance of adhering to the once weekly
intakes as incorrect intake of methotrexate can lead to severe, including
potentially lethal, side effects, especially in elderly patients.
• Due to the risk of severe potentially life-threatening adverse reactions
(drug product) should only be used in patients with severe active
rheumatoid arthritis or severe forms of psoriasis vulgaris including
chronic plaque psoriasis, erythrodermic psoriasis, psoriatic arthritis and
pustular psoriasis which are not responsive to other conventional
Warnings regarding all indications
Patients undergoing methotrexate therapy should be closely monitored to
prevent intoxication and to ensure fast identification of toxic side effects.
Especially strict monitoring of the patient is indicated following prior
radiotherapy (especially of the pelvis), functional impairment of the
haematopoietic system (e.g., following prior radio- or chemotherapy),
impaired general condition as well as advanced age and in very young
children. Patients should be fully informed by the physician about risks and
benefits of the therapy, of the need to inform the physician immediately if
toxic signs occur and about necessary examinations and safety measures
during treatment. Discontinuation of methotrexate therapy did not always
result in a complete recovery from toxic effects.
Recommended examinations and safety measures
Before initiating therapy

Before administration of methotrexate, the following check-up examinations
and safety precautions are recommended:
• renal and hepatic function tests
• a complete blood picture
• urinalysis should be performed as part of the prior and follow-up
• chest x-ray
• hepatitis A, B, C serology
• tuberculosis diagnostics
Strict monitoring is necessary in patients with pulmonary dysfunction.
Especially strict monitoring of the patient is indicated following prior
radiotherapy (especially of the pelvis), functional impairment of the
haematopoietic system (e.g. following prior radio- or chemotherapy), impaired
general condition as well as advanced age and in very young children.
During Therapy
The following examinations should be performed:
Monitoring of the serum concentration of methotrexate as a factor of the
dosage for the therapy protocol used.
Regular check-ups of the oral cavity and the pharynx for changes in the
mucus membranes. Ulceration mainly precedes a decrease in the number of
leucocytes and/or thrombocytes.
Regular leucocyte and thrombocyte counts have to be taken.
A complete blood picture has to be taken regularly.
Regular testing of hepatic and renal function, especially at higher doses
should be performed. Creatinine, urea and electrolytes have to be checked on
days 2 and 3 to identify any threatening impairment of methotrexate
elimination at an early stage.
In the case of long-term therapy, if deemed necessary, bone marrow biopsies
have to be taken.
Preparations for a possible blood transfusion should be made
Patients should report all symptoms and signs suggestive of infection,
especially sore throat.
Laboratory analysis should be repeated at least every 2 months in the course of
treatment with methotrexate.
For patients treated for psoriasis or psoriatic arthritis
The tests in the above table should be performed
a) weekly in the first two weeks of treatment;
b) every second week for the next month and
c) thereafter once a month depending on the individual leucocyte count and stability
of the patient

Liver biopsies may also be required. In case of treatment for longer periods, for
psoriasis and psoriatic arthritis, liver biopsies should be taken since liver function
tests may frequently be normal in the development stage of liver cirrhosis and liver
damage can only be recognized with liver biopsies. With regard to the necessity of
liver biopsies patients should be grouped in low and high risk patients.
Patients without risk factors: Liver biopsy is not necessary in patients receiving less
than a total of 1.0 to 1.5 g.
Patients with risk factors:

History of alcohol abuse

Persistent elevation of liver enzymes

History of liver disease including hepatitis B or C

Family history of liver disease.

For these patients liver biopsy is recommended at or shortly after initiation of the
therapy. Since a small percentage of patients discontinue treatment after 2-4 months,
the first liver biopsy may be postponed after the initial therapy has been finalized.
Recurrent liver biopsies should be taken after a total dose of 1.0 to 1.5 g has been
Liver biopsy may not be performed in:

elderly patients,

patients with acute diseases

patients contraindicated for liver biopsy

patients with low expectation of life.

The result of the liver biopsy is crucial for the decision whether the therapy can be
continued or not. Methotrexate therapy should be discontinued in any patient having a
liver biopsy which shows moderate to severe liver damage, persistent elevated liver
function tests or in patients refusing the liver biopsy.
Strict monitoring is necessary in patients with pulmonary dysfunction, smokers
and/or patients with certain bronchopulmonary diseases, particularly bronchiectasis or
fibrosis. It is recommended to perform lung function tests prior to initiating treatment.
In all cases, a chest x-ray should be performed before starting treatment with
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.

Reversible eosinophilic pulmonary reactions and treatment-resistant, interstitial
fibrosis may occur, particularly after long-term treatment.
Methotrexate elimination is reduced in patients with pathologic fluid accumulation
(third space fluids) such as ascites or pleural effusions that may lead to prolonged
methotrexate plasma elimination half-life and unexpected toxicity. Patients with
pleural effusions and ascites should be drained prior to initiation of methotrexate
therapy. Methotrexate dose should be reduced according to the serum methotrexate
Acute or chronic pneumonitis, often associated with blood eosinophilia, may occur
and deaths have been reported. Symptoms typically include dyspnoea, cough
(especially a dry 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
Because of its immunosuppressive properties, methotrexate may increase the risk of
infectious complications including potentially fatal opportunistic infections, including
Pneumocystis carinii pneumonia. Therefore it is important to:

Identify primary focal sites and, if necessary, eradicate them before initiating

Ensure regular monitoring, as infections may occur at any time during treatment.

Lung manifestations of RA and other connective tissue disorders are recognised to
occur. In patients with RA, the physician should be specifically alerted to the
potential for methotrexate induced adverse effects on the pulmonary system.
Hepatic toxicity has been observed, usually associated with chronic hepatic disease.
The administration of low doses of methotrexate for prolonged periods may give rise,
in particular, to hepatic toxicity. Liver function should be closely monitored. If
hepatic function abnormalities develop, methotrexate dosing should be suspended for
at least two weeks. It is only appropriate to restart methotrexate provided the
abnormalities return to normal and the re-exposure is deemed appropriate.
Due to its hepatotoxic potential it is recommended that patients abstain from or at
least significantly reduce alcohol use. In addition, patients should not receive
concomitantly other hepatotoxic or potentially hepatotoxic drugs.
Patients with insulin-dependent diabetes should only cautiously be treated with
methotrexate since cases of liver cirrhosis without intermittent increases in liver
enzymes have been reported.

Particular care and possible cessation of treatment are indicated if stomatitis or GI
toxicity occurs as haemorrhagic enteritis due to the danger of potentially fatal
intestinal perforation.
Conditions leading to dehydration like vomiting, diarrhoea or stomatitis can increase
toxic effects due to elevated methotrexate levels. In these cases a supportive treatment
should be implemented and discontinuation of methotrexate treatment should be
Reversible eosinophilic pulmonary reactions and treatment-resistant, interstitial
fibrosis may occur, particularly after long-term treatment.
Renal lesions may develop if the urinary flow is impeded and urinary pH is low,
especially if large doses have been administered.
Renal function should be closely monitored before, during and after treatment.
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 by oral or intravenous
administration of sodium bicarbonate (5 x 625mg tablets every three hours) is
recommended as a preventative measure.
Blood, Infection and Immunosuppression
Haematopoietic suppression caused by methotrexate may occur abruptly and with
apparently safe dosages. Full blood counts should be closely monitored before, during
and after treatment. If a clinically significant drop in white cell or platelet count
develops, methotrexate therapy should be withdrawn immediately and appropriate
supportive therapy given (see section 4.8, Undesirable Effects). Initial clinical signs
for life-threatening complications of severe cytopenia include fever, sore throat, oral
ulcerations, flu-like symptoms, nasal and dermal bleedings. Patients should be
advised to report all symptoms or signs suggestive of infection.
Methotrexate has some immunosuppressive activity and therefore the immunological
response to concurrent vaccination may be decreased. In addition, concomitant use of
a live vaccine could cause severe antigenic reaction and is therefore contraindicated
(see 4.3).
The immunosuppressive effect of methotrexate should be taken into account when
immune responses of patients are important or essential. Special attention should be
paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis
B or C) because of their potential activation.

Methotrexate should be used with extreme caution in patients with infection,
haematological depression, renal impairment, diarrhoea, ulcerative disorders of the GI
tract and psychiatric disorders. If profound leukopenia occurs during therapy,
bacterial infection may occur and become a threat.
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 cytotoxic therapy. There have been
reports on the manifestation of lymphomas which were, in some cases, reversible
after discontinuing methotrexate therapy. In a recent study, no increased incidence in
the manifestation of lymphomas during the course of methotrexate treatment could be
detected. Furthermore, the potential of methotrexate to produce other cancers in
humans has been evaluated in several studies, but the results do not confirm a
carcinogenic risk.
Methotrexate has been reported to cause impairment of fertility, oligospermia,
menstrual dysfunction and amenorrhoea in humans, during and for a short period
after cessation after therapy. 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 childbearing potential (see section
Following administration to a man or woman conception should be avoided by using
an effective contraceptive method for at least 6 months after using Methotrexate Oral
Solution (see section 4.3, Contraindications).
Skin toxicity
Severe, occasionally fatal, dermatologic reactions, including toxic epidermal
necrolysis (Lyell’s Syndrome) or Stevens-Johnson syndrome have been reported after
single or multiple doses of methotrexate.
Psoriatic lesions may worsen if patients on methotrexate therapy receive UV
radiation. Due to risk of phototoxicity the patients must avoid sunlight and solarium.
Folic acid supplementation:
If acute methotrexate toxicity occurs, patients may require treatment with folinic acid.
In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid
supplementation may reduce methotrexate toxicity, such as gastrointestinal
symptoms, stomatitis, alopecia and elevated liver enzymes.
It is recommended to check levels of vitamin B12 prior to initiating folic acid
supplementation, particularly in adults aged over 50 years, as folic acid intake may
mask a vitamin B12 deficiency.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft
tissue necrosis and osteonecrosis.
Excipient Warnings
This product contains:
Sodium Methyl and Ethyl Parahydroxybenzoate (E219 and E215) – May cause
allergic reactions (possibly delayed)
Sodium – Contains 0.72mg/ml. To be taken into consideration by patients on a
controlled sodium diet
Sulphites (from the flavour) – May rarely cause severe hypersensitivity reactions and


Interaction with other medicinal products and other forms of interaction
After absorption methotrexate binds partly to serum albumin. Salicylates,
amidopyrine derivatives, phenylbutazone, diphenylhydantoin (phenytoin),
barbiturates, tranquillisers, tetracyclines, sulphonamides, doxorubicin, probenecid, paminobenzoic acid, antidiabetic agents and diuretics displace methotrexate bound to
the plasma protein and can increase its toxicity. Therefore great caution should be
exercised when these medicinal products are coadministered with methotrexate.
Risk of exacerbation of convulsions resulting from the decrease of phenytoin
digestive absorption by cytotoxic drug or risk of toxicity enhancement or loss of
efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.
In the case of pre-treatment with medicinal products exhibiting myelosuppressive or
immunosuppressive effects (e.g. cytostatics, sulphonamides, chloramphenicol,
diphenylhydantoin, amidopyridine derivatives), it is possible to observe enhancement
of bone marrow toxicity and immunosuppression. Bone marrow suppression and
reduced folate concentrations have been reported when triamterene and methotrexate
were coadministered. Trimethoprim/sulfamethoxazole has been reported in rare cases
to increase bone marrow suppression in patients treated with methotrexate,
presumably because of the increased antifolate effect.
The application of pyrimethamine and cotrimoxazole (trimethoprim) in combination
with methotrexate can cause acute megaloblastic pancytopenia, probably due to
additive inhibition of the dihydrofolic acid reductase.
Sequential use of methotrexate and 5-fuorouracil may result in synergistic
enhancement of cytotoxic effects.

Penicillins (e.g. amoxicillin, carbenicillin, mezlocillin) can decrease the renal
clearance of methotrexate in some cases and haematological and gastrointestinal
toxicity has been observed in combination with high- and low-dose methotrexate.
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.
Coadministration of other, potentially nephro- and hepatotoxic agents (e.g.
sulfasalazine, leflunomide and alcohol) with methotrexate should be avoided.
Special caution should be exercised when observing patients receiving methotrexate
therapy in combination with azathioprine or retinoids.
Methotrexate in combination with leflunomide can increase the risk for pancytopenia.
Enhancement of nephrotoxicity may be seen with high-dose methotrexate is
administered in combination with a potentially nephrotoxic chemotherapeutic agent
(e.g. cisplatin).
NSAIDs should not be administered before or concurrently with high-dose
methotrexate. Concomitant use of some NSAIDs and high-dose methotrexate has
been reported to increase and prolong the serum methotrexate concentration in serum
and to increase gastrointestinal and haematological toxicity. When using smaller
doses of methotrexate, these medicinal products have been found in animals to
decrease the tubular secretion of methotrexate and possibly to increase its toxicity. In
addition to methotrexate, patients with rheumatoid arthritis have generally been
treated, however, with NSAIDs with no problems. It should be noted, however, that
the doses of methotrexate used in the treatment of rheumatoid arthritis (7.5 – 15
mg/week) are slightly lower than those used for psoriasis and that higher doses can
result in unexpected toxicity.
In the presence of an existing folic acid deficiency, the toxicity of methotrexate is
increased, the efficacy of therapy can be impaired by tetrahydrofolic acid
preparations. Vitamin preparations containing folic acid or its derivatives may change
the response
to methotrexate.
There is evidence that coadministration of methotrexate and omeprazole prolongs the
elimination of methotrexate via the kidneys. Coadministration of proton pump
inhibitors, such as omeprazole or pantoprazole, can cause interactions.

Methotrexate may decrease the clearance of theophylline; theophylline levels should
be monitored when used concurrently with methotrexate.
Methotrexate may increase the bioavailability and plasma levels of mercaptopurine.
By interference with first-pass metabolism. Combinations of methotrexate and
mercaptopurine may therefore require dose adjustment.
Vaccination with a live vaccine in patients receiving chemotherapeutic agents may
result in severe and fatal infections. Concomitant use with a live vaccine is contraindicated (see Section 4.3)
Cyclosporine may potentiate methotrexate efficacy and toxicity. There is a risk of
excessive immunosuppression with risk of lymphoproliferation when the combination
is used.
Cholestyramine can increase the non-renal elimination of methotrexate by
interrupting the enterohepatic circulation.
The application of procarbazine during high-dose methotrexate therapy increases the
risk of impairment or renal function.
Patients receiving concomitant therapy with methotrexate and acitretin or other
retinoids should be monitored closely for any possible increased risk of
In patients receiving methotrexate therapy, treated for a cutaneous herpes zoster with
adrenocortical steroids, in isolated cases, disseminated herpes zoster manifested.
The use of nitrous oxide-based anaesthetics intensifies the effect of methotrexate on
folic acid metabolism and leads to severe unpredictable myelosuppression and
stomatitis. This can be reduced by the administration of calcium folinate.
Concomitant application of L-asparaginase is antagonistic towards the effects of
Concomitant use of other medicinal products with nephrotoxic and hepatotoxic
potential (including alcohol) should be avoided.
Care should be taken when erythrocyte concentrates are administered concomitantly
with methotrexate. In patients infused with methotrexate over 24 hours and who

subsequently received blood transfusions, increased toxicity was observed, caused by
prolonged high serum concentrations of methotrexate.


Fertility, pregnancy and lactation
Methotrexate is contraindicated during pregnancy in non-oncological indications (see
section 4.3). In animal studies, methotrexate has been shown reproductive toxicity
(see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has
been reported to cause fetal death and/or congenital abnormalities. Exposure of a
limited number of pregnant women (42) resulted in an increased incidence (1:14) of
malformations (cranial, cardiovascular and extremital). If methotrexate is
discontinued prior to conception, normal pregnancies have been reported.
In women of child-bearing age, any existing pregnancy must be excluded with
certainty by taking appropriate measures, e.g. a pregnancy test, prior to initiating
therapy. Women must not get pregnant during methotrexate therapy and patients of a
sexually mature age (women and men) must use effective contraception during
treatment with methotrexate and at least 6 months thereafter (see section 4.4). If
nevertheless, pregnancy occurs during this period, medical advice should be given
regarding the risk of harmful effects on the child associated with treatment.
As methotrexate is genotoxic, all women who wish to become pregnant are advised to
consult a genetic counselling centre, if possible, already prior to therapy, and men
should seek advice about the possibility of sperm preservation before starting therapy.
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 this methotrexate the patient should be informed of the potential risk to
the foetus.
As methotrexate passes into breast milk and may cause toxicity in nursing infants,
treatment is contraindicated during the lactation period (see section 4.3). If use during
the lactation period should become necessary, breast-feeding is to be stopped prior to
starting treatment.
Animal studies show that methotrexate impairs fertility.
Both men and women receiving methotrexate should be informed of the potential risk
of adverse effects on reproduction. Women of childbearing potential should be fully

informed of the potential hazard to the foetus should they become pregnant during
methotrexate therapy.


Effects on ability to drive and use machines
Central nervous symptoms such as tiredness and dizziness can occur during
treatment, therefore in isolated cases methotrexate can have minor or moderate
influence on the ability to drive and use machines.


Undesirable effects
In general, the incidence and severity of side effects are considered to be dose-related.
In the antineoplastic treatment myelosuppression and mucositis are the predominant
dose-limiting toxic effects of methotrexate. The severity of these reactions depends
on the dose, mode and duration of application of methotrexate. Mucositis generally
appears about 3 to 7 days after methotrexate application, leucopenia and
thrombocytopenia follow a few days later. In patients with unimpaired elimination
mechanisms, myelosuppression and mucositis are generally reversible within 14 to 28
The most common undesirable effects are ulcerative stomatitis, leucopenia,
thrombocytopenia, nausea, vomiting, anorexia, and abdominal discomfort. Especially
during the first 24 - 48 hours after methotrexate administration decreased creatinine
clearance and increase in liver enzymes (ALT, AST, alkaline phosphatase, bilirubin)
If adverse reactions occur, the dose should be reduced or therapy discontinued and
necessary corrective therapeutic measures undertaken, such as administration of
calcium folinate (see sections 4.2 and 4.4). Methotrexate therapy should only be
resumed with caution, under close assessment of the necessity for treatment and with
increased alertness for possible reoccurrence of toxicity.
Methotrexate has the potential for serious, sometimes fatal toxicity. The toxic effects
may be related in frequency and severity to the dose of frequency of administration
but have been seen at all doses. Because the toxic reactions can occur at any time
during therapy, the patients have to be observed closely and must be informed of
early signs and symptoms of toxicity.
In the treatment of rheumatoid arthritis, methotrexate induced lung disease is a
potentially serious adverse drug reaction which may occur acutely at any time during
therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
The frequencies of the adverse reactions are classified as follows: Very common
(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000

to <1/1000); very rare (<1/10000), not known (cannot be estimated from the available
data). <1/1000); very rare (<1/10000), not known (cannot be estimated from the
available data). Within each frequency grouping, undesirable effects are presented in
order of decreasing seriousness. Adverse reactions for the various systems are as

Infections and

malignant and
(including cysts
and polyps)
Blood and

Immune system
Nervous system


(sometimes fatal)

Herpes Zoster.

Very Rare
Herpes simplex Hepatitis

Not Known
Disseminated herpes
simplex. Nocardiosis.




Irritation. Dysarthria.
Aphasia. Lethargy.
Pain. Muscular asthenia
or paraesthesia in the
Convulsions. Transient
subtle cognitive
dysfunction. Mood
alteration. Unusual
cranial sensations.
Psychoses. Cerebral
oedema. Tinnitus.
Conjunctivitis. Blurred
Pericardial effusion.
Pericarditis. Pericardial


Lymphoma (can be
reversible see 4.4)


Bone marrow

Diabetes mellitus.




Eye disorders


thoracic and

pneumonitis (can
be fatal).
Interstitial fibrosis.





Pharyngitis (see
section 4.4).

ulcerations and
periportal fibrosis,

Pneumocystis carinii –
pneumonia. Chronic
interstitial obstructive
lung disease. Pleuritis.
Dry cough.
Pancreatitis. Toxic

Impaired vision.

and bilirubin

Skin and
tissue disorders


liver cirrhosis,
acute hepatitis,
hepatic necrosis,
which may be fatal
in chronic
Potentially lifethreatening severe
skin reactions like
syndrome, Toxic
dermatitis, skin
necrosis, vasculitis
and extensive
herpetiform skin
eruptions which
mostly recover

Acne. Erythema
changes. Urticaria.
Lesions of
psoriasis may
worsen with
concomitant UV
therapy. Skin
ulceration (mainly
in psoriasis) and
erosion of psoriatic
plaques. Radiation
dermatitis and
sunburn may be
of the nails.

and connective
tissue disorders

Renal and


system and
breast disorders.

inflammation and

Ecchymoses. Acute
paronychia and

Osteoporosis including
aseptic necrosis of the
femoral head.
Arthralgia. Myalgia.
Increased rheumatic
Dysuria. Azotaemia.
Cystitis. Haematuria.

Decreased libido.

Formation of defective
oocytes or sperm cells.
Transient oligospermia,
infertility. Vaginal

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 at:’


Leucovorin is a specific antidote for methotrexate and, following accidental
overdosage, should be administered within one hour at a dosage equal to, or greater
than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further

doses may be required. The patient should be observed carefully and blood
transfusions, renal dialysis (see below) and reverse barrier nursing may be necessary.
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.
Effective clearance of methotrexate has been reported with acute, intermittent
haemodialysis using a high flux dialyser. Peritoneal dialysis has not been shown to
improve methotrexate elimination.
Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly
intake of oral methotrexate have been reported. In these cases, symptoms that have
been commonly reported are haematological and gastrointestinal reactions.




Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents,
antimetabolites, Folic acid analogues; ATC code: L01BA01
Methotrexate (4-amino-10-methylfolic acid) is a folic acid antagonist which inhibits
the reduction of folic acid and increase of tissue cells. Methotrexate enters the cell
through an active transport mechanism of reduced folates. As a result of
polyglutamation of methotrexate caused by the folylpolyglutamylate enzyme, the
duration of the cytotoxic effect of the drug substance in the cell increases.
Methotrexate is a phase-specific substance the main action of which is directed to the
S-phase of cell mitosis. It acts generally most effectively on actively increasing
tissues, such as malignant cells, bone marrow, fetal cells, skin epithelium, oral and
intestinal mucosa as well as urinary bladder cells. As the proliferation of malignant
cells is higher than that of most normal cells, methotrexate can slow down the
proliferation of malignant cells without causing, however, irreversible damage to
normal tissue.
Calcium folinate is a folinic acid which is used to protect normal cells from the toxic
effects of methotrexate. Calcium folinate enters the cell through a specific transport
mechanism, is converted in the cell into active folates and reverses the inhibition of
the precursor synthesis caused by the DNA and RNA.


Pharmacokinetic properties
The effect of orally administered methotrexate seems to be dependent on the size of
the dose. Peak concentrations in serum are reached within 1–2 hours. Generally a
dose of methotrexate of 30 mg/m2 or less is absorbed rapidly and completely. The
bioavailability of orally administered methotrexate is high (80–100%) at doses of 30
mg/m2 or less. Saturation of the absorption starts at doses above 30 mg/m2 and
absorption at doses exceeding 80 mg/m2 is incomplete.
The drug is actively transported across cell membranes and is bound as polyglutamate
conjugates. The drug is widely distributed into body tissues with the highest
concentrations in the kidneys, gallbladder, spleen, liver, skin, colon and small
intestine. The drug may remain in the body for several months, particularly in the
liver. As the drug penetrates ascetic fluid and effusions, these spaces may act as
The drug undergoes hepatic and intracellular metabolism to polyglutamated forms,
which can be converted back to methotrexate by hydrolase enzymes. Small amounts
of these active metabolites may be converted to 7-hydroxymethotrexate.The
accumulation of this metabolite may become substantial following the administration
of high doses. The clearance of methotrexate form the serum is reported to be
triphasic and the terminal elimination half-life is within a range of 3 – 10 hours for
patients receiving methotrexate for rheumatoid arthritis, psoriasis or who have
received low-dose methotrexate antineoplastic therapy. In patients receiving highdose methotrexate, the elimination half-life is within the range between 8 and 15
hours. The drug is eliminated primarily in the urine by glomerular filtration and active
tubular secretion. Approximately 41% of the dose is excreted unchanged in the urine
within the first six hours, 90% within 24 hours. A minor part of the dose is excreted
in the bile of which there is pronounced enterohepatic circulation.
Delayed drug clearance has been reported to be one of the major reasons for
methotrexate toxicity. Excretion is impaired and accumulation occurs more rapidly in
patients with impaired renal function, pleural effusions, or those with other “thirdspace” compartments (e.g. ascites).
Approximately 50% of the drug is bound to serum proteins and laboratory studies
demonstrate that the drug may be displaced from plasma albumin by various
compounds, including sulphonamides, salicylates, tetracyclines, chloramphenicol and
Methotrexate crosses the placental barrier and is distributed into breast milk.


Preclinical safety data
Chronic toxicity
Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of
gastrointestinal lesions, myelosuppression and hepatotoxicity.
Mutagenic and carcinogenic potential
Long-term studies in rats, mice and hamsters did not show any evidence of a
tumorigenic potential of methotrexate. Methotrexate induces gene and chromosome
mutations both in vitro and in vivo. A mutagenic effect is suspected in humans.
Reproductive toxicology
Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In
rhesus monkeys, no malformations comparable to humans occurred.




List of excipients
Sodium Methyl Parahydroxybenzoate E219
Sodium Ethyl Parahydroxybenzoate E215
Disodium Hydrogen Phosphate Dihydrate E339
Citric Acid Monohydrate E330
Sucralose E955
Raspberry Flavour (containing propylene glycol and sulphites)
Purified Water


None stated


Shelf life
18 months.
After first opening, the product may be stored for a maximum of 28 days.


Special precautions for storage
Do not store above 25°C. Do not refrigerate. Store in the original carton in order to
protect from light.


Nature and contents of container
Bottle: Amber (Type III glass)

35ml, or 65ml, cartonned with an oral dosing device (LDPE body, white
polystyrene plunger with a capacity of 10ml, major dosage graduation at every
1ml, minor dosage graduation at every 0.25ml) and a bottle adaptor (low density

Closure: HDPE, EPE wadded, child resistant closure. White HDPE cap with PE liner;
child resistant and tamper evident
Not all pack sizes may be marketed.


Special precautions for disposal
Safe handling
Anyone handling methotrexate should wash their hands before and after
administering a dose. To decrease the risk of exposure, parents and care givers
should wear disposable gloves when handling methotrexate.
Contact with skin or mucous membrane must be avoided. If methotrexate
comes into contact with skin or mucosa, it should be washed immediately and
thoroughly with soap and water.
Spillages must be wiped immediately.
Women who are pregnant, planning to be or breastfeeding should not handle
Parents / care givers and patients should be advised to keep methotrexate out
of the reach and sight of children, preferably in a locked cupboard.
Accidental ingestion can be lethal for children.
Keep the bottle tightly closed to protect the integrity of the product and
minimise the risk of accidental spillage.

Any unused medicinal product or waste material should be disposed of in
accordance with local requirements.
Instructions for use of the syringe provided with the pack, or as directed by the
healthcare professional:
• Open the bottle: press the cap and turn it anticlockwise (Figure 1).
• Insert the syringe adaptor into the bottle neck (Figure 2).
• Take the syringe and put it in the adaptor opening (Figure 3).
• Turn the bottle upside down (Figure 4).
• Fill the syringe with a small amount of solution by pulling the piston down
(Figure 4A). Then push the piston upward in order to remove any possible
bubbles (Figure 4B). Finally, pull the piston down to the graduation mark
corresponding to the quantity in millilitres (ml) prescribed by your doctor.
The top flat edge of the piston should be in line with the graduation mark
you are measuring to (Figure 4C).
• Turn the bottle the right way up (Figure 5A).
• Remove the syringe from the adaptor (Figure 5B).
• Put the end of the syringe into your mouth and push the piston slowly back
in to take the medicine. Alternatively, dispense the solution onto a spoon
or into a small glass of water and take your medicine straight away.
• Once the dose has been swallowed, a glass of water should be drunk to
remove any methotrexate residue from the oral cavity.
• Close the bottle with the plastic screw cap - leave the syringe adaptor in
the bottle.
• Wash the syringe with warm ‘soapy’ water and rinse well. Hold the
syringe under water and move the plunger up and down several times to
make sure the inside of the syringe is clean. Let the syringe dry completely
before you use that syringe again for dosing. Store the syringe in a
hygienic place with the medicine. (Figure 6.)
water IMMEDIATELY after use.


Rosemont Pharmaceuticals Ltd
Rosemont House
Yorkdale Industrial Park
Braithwaite Street
LS11 9XE


PL 00427/0233





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