Metoject is indicated for the treatment of
 active rheumatoid arthritis in adult patients,
 polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal
anti-inflammatory drugs (NSAIDs) has been inadequate,
 severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy
such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients.
 mild to moderate Crohn’s disease either alone or in combination with corticosteroids in adult patients
refractory or intolerant to thiopurines.

Important warning about the dosage of Metoject (methotrexate)
In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and psoriatic arthritis, and
Crohn’s disease, Metoject (methotrexate) must only be used once a week. Dosage errors in the use of
Metoject (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

Metoject should only be prescribed by physicians, who are familiar with the various characteristics of the
medicinal product and its mode of action. The administration should routinely be done by health
professionals. If the clinical situation permits the treating physician can, in selected cases, delegate the
subcutaneous administration to the patient her/himself. Patients must be educated and trained in the
proper injection technique when self-administering methotrexate. The first injection of Metoject should
be performed under direct medical supervision. Metoject is injected subcutaneously once weekly.
The patient is to be explicitly informed about the fact of administration once weekly. It is advisable to
determine a fixed, appropriate weekday as day of injection.
Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions).
Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some
cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).
Dosage in adult patients with rheumatoid arthritis:
The recommended initial dose is 7.5 mg of methotrexate once weekly, administered subcutaneously.
Depending on the individual activity of the disease and tolerability by the patient, the initial dose may be
increased gradually by 2.5 mg per week. A weekly dose of 25 mg should in general not be exceeded.
However, doses exceeding 20 mg/week are associated with significant increase in toxicity, especially
bone marrow suppression. Response to treatment can be expected after approximately 4 – 8 weeks. Upon
achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible
effective maintenance dose.
Dosage in children and adolescents below 16 years with polyarthritic forms of juvenile idiopathic arthritis
The recommended dose is 10-15 mg/m² body surface area (BSA)/once weekly, administered by
subcutaneous injection. In therapy-refractory cases the weekly dosage may be increased up to 20mg/m2
body surface area/once weekly. However, an increased monitoring frequency is indicated if the dose is
increased.
Patients with JIA should always be referred to a rheumatology specialist in the treatment of
children/adolescents.
Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is
available for this population (see section 4.4).
Dosage in patients with psoriasis vulgaris and psoriatic arthritis:
It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to
therapy to detect idiosyncratic adverse reactions. The recommended initial dose is 7.5 mg of methotrexate
once weekly, administered subcutaneously. The dose is to be increased gradually but should not, in
general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be
associated with significant increase in toxicity, especially bone marrow suppression. Response to
treatment can generally be expected after approximately 2 – 6 weeks. Upon achieving the therapeutically
desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose.
Dosage in patients with Crohn’s disease
 Induction treatment:
25 mg/week administered subcutaneously.
Response to treatment can be expected after approximately 8 to 12 weeks.
 Maintenance treatment:
15 mg/week administered subcutaneously.

There is not sufficient experience in the paediatric population to recommend Metoject for the treatment of
Crohn’s disease in this population.
Maximum weekly dose
The dose should be increased as necessary but should in general not exceed the maximum recommended
weekly dose of 25 mg. In a few exceptional cases a higher dose might be clinically justified, but should
not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase.
Patients with renal impairment:
Metoject should be used with caution in patients with impaired renal function. The dose should be
adjusted as follows:
Creatinine clearance (ml/min) Dose
> 60 100 %
30 – 59 50 %
< 30 Metoject must not be used
See section 4.3.
Patients with hepatic impairment:
Methotrexate should be administered with great caution, if at all, to patients with significant current or
previous liver disease, especially if due to alcohol. If bilirubin is  5 mg/dl (85.5 μmol/l), methotrexate is
contraindicated.
For a full list of contraindications, see section 4.3.
Use in elderly patients:
Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well
as lower folate reserves which occur with increased age.
Use in patient with a third distribution space (pleural effusions, ascitis):
As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a
third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration
may be required (see section 5.2 and 4.4).
Method of administration:
The medicinal product is for single use only.
Metoject is given by the subcutaneous route in children and adults. See section 6.6 for instructions for
subcutaneous use.
The overall duration of the treatment is decided by the physician.
Note:
If changing the oral application to parenteral administration a reduction of the dose may be required due
to the variable bioavailability of methotrexate after oral administration.
Folic acid supplementation may be considered according to current treatment guidelines.

Metoject is contraindicated in the case of  hypersensitivity to the active substance or to any of the excipients listed in section 6.1,  severe liver impairment (see section 4.2),  alcohol abuse,  severe renal impairment (creatinine clearance less than 30 ml/min., see section 4.2 and section 4.4),  pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia,  serious, acute or chronic infections such as tuberculosis, HIV or other immunodeficiency syndromes,  ulcers of the oral cavity and known active gastrointestinal ulcer disease,  pregnancy, breast-feeding (see section 4.6),  concurrent vaccination with live vaccines.

Patients must be clearly informed that the therapy has to be administered once a week, not every day.
Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic
effects or adverse reactions may be detected and evaluated with minimal delay. Therefore methotrexate
should be only administered by, or under the supervision of physicians whose knowledge and experience
includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic
reactions, the patient should be fully informed by the physician of the risks involved and the
recommended safety measures.

Recommended examinations and safety measures
Before beginning or reinstituting methotrexate therapy after a rest period:
Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum
albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.
During therapy (at least once a month during the first six months and every three months thereafter):
An increased monitoring frequency should be considered also when the dose is increased.
1. Examination of the mouth and throat for mucosal changes
2. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused
by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in whitecell
or platelet counts indicates immediate withdrawal of the medicinal product and appropriate
supportive therapy. Patients should be advised to report all signs and symptoms suggestive of
infection. Patients taking simultaneous administration of haematotoxic medicinal products (e.g.
leflunomide) should be monitored closely with blood count and platelets.
3. Liver function tests: Particular attention should be given to the appearance of liver toxicity.
Treatment should not be instituted or should be discontinued if any abnormality of liver function
tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to
normal within two weeks after which treatment may be recommenced at the discretion of the
physician. There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in
rheumatological indications.
For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. Further
research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen

can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and
differentiate between patients with no risk factors and patients with risk factors such as excessive
prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family
history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to
hepatotoxic drugs or chemicals and prolonged Methotrexate treatment or cumulative doses of 1.5 g
or more.
Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three
times of the upper limit of normal have been reported by patients at a frequency of 13 – 20 %. In the
case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of
therapy should be taken into consideration.
Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not
be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol
should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be
exercised in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide).
The same should be taken into account with the simultaneous administration of haematotoxic
medicinal products (e.g. leflunomide).
4. Renal function should be monitored by renal function tests and urinanalysis (see sections 4.2
and 4.3).
As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be
expected in the case of renal impairment, which may result in severe undesirable effects.
Where renal function may be compromised (e.g. in the elderly), monitoring should take place more
frequently. This applies in particular, when medicinal products are administered concomitantly, that
affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal anti-inflammatory
medicinal products) or that can potentially lead to impairment of blood formation. Dehydration may
also intensify the toxicity of methotrexate.
5. Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if
necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of
methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific
pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous
lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial
pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported.
Although clinically variable, the typical patient with methotrexate-induced lung disease presents
with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be
excluded. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate
therapy. This lesion can occur at all doses. 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.
6. Methotrexate may, due to its effect on the immune system, impair the response to vaccination results
and affect the result of immunological tests. Particular caution is also needed in the presence of
inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of eventual
activation. Vaccination using live vaccines must not be carried out under methotrexate therapy.

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.
Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been
reported to cause an acute megaloblastic pancytopenia in rare instances.
Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction).
Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.
Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions).
Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some
cases, discontinuation of methotrexate administration. Pleural effusions and ascites should be drained
prior to initiation of methotrexate treatment (see section 5.2).
Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise
haemorrhagic enteritis and death from intestinal perforation may occur.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease
the effectiveness of methotrexate.
For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis
which is not adequately responsive to other forms of therapy, but only when the diagnosis has been
established by biopsy and/or after dermatological consultation.
Encephalopathy leukoencephalopathy have been reported in oncologic patients receiving methotrexate
therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.
Fertility and reproduction
Fertility
Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in
humans, during and for a short period after cessation of therapy, and to cause impaired fertility, 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 defects in humans. Therefore, the possible risks
of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female
patients of childbearing potential (see section 4.6). The absence of pregnancy must be confirmed before
Metoject is used. If women of a sexually mature age are treated, effective contraception must be
performed during treatment and for at least six months after.
For contraception advice for men see section 4.6.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially
“sodium-free”.
Paediatric population

Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are
available for this population (see section 4.2).

Nitrous oxide
The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased
toxicity such as severe, unpredictable myelosuppression, and stomatitis. Whilst this effect can be reduced
by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be
avoided.
Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products
The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol
consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4).
Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be
monitored with special care. The same should be taken into account with the simultaneous administration
of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine). The
incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with
methotrexate.
Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of
hepatotoxicity.
Oral antibiotics
Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can
interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the
bacterial metabolism.
Antibiotics
Antibiotics, like penicillines, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual
cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate
with simultaneous haematological and gastro-intestinal toxicity may occur.
Medicinal products with high plasma protein binding
Methotrexate is plasma protein bound and may be displaced by other protein bound medicinal products
such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines,
chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to
increased toxicity when used concurrently.
Probenecid, weak organic acids, pyrazoles and non-steroidal anti-inflammatory agents
Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the
elimination of methotrexate and higher serum concentrations may be assumed inducing higher
haematological toxicity. There is also a possibility of increased toxicity when low dose methotrexate and
non steroidal anti-inflammatory medicinal products or salicylates are combined.
Medicinal products with adverse reactions on the bone marrow
In the case of medication with medicinal products which may have adverse reactions on the bone marrow
(e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention
should be paid to the possibility of pronounced impairment of blood formation.

Medicinal products which cause folate deficiency
The concomitant administration of products which cause folate deficiency (e.g. sulphonamides,
trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore
advisable in the presence of existing folic acid deficiency.
Products containing folic acid or folinic acid
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease
the effectiveness of methotrexate.
Other antirheumatic medicinal products
An increase in the toxic effects of methotrexate is, in general, not to be expected when Metoject is
administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds,
penicillamine, hydroxychloroquine, sulfasalazine, azathioprin, cyclosporin).
Sulfasalazine
Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of
methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through
sulphasalazine, such undesirable effects have only been observed in rare individual cases in the course of
several studies.
Mercaptopurine
Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and
mercaptopurine may therefore require dose adjustment.
Proton-pump inhibitors
A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to
interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal
elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the
metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.
Theophylline
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when
used concurrently with methotrexate.
Caffeine- or theophylline-containing beverages
An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing
soft drinks, black tea) should be avoided during methotrexate therapy.

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 30 mg/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 30 mg/week), compared to a reported rate of 22.5% in disease-matched
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 30 mg/week) during pregnancy, compared to approximately 4% of live births in
disease-matched patients treated with drugs other than methotrexate.
Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but
higher rates of spontaneous abortions and congenital malformations are expected.
When methotrexate was discontinued prior to conception, normal pregnancies have been reported.
Breast-feeding
Methotrexate is excreted in human milk. Because of the potential for serious adverse reactions in breastfed
infants, Metoject is contraindicated during breast-feeding (see section 4.3). Therefore breast-feeding
must be discontinued prior to and throughout administration.
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.

Central nervous symptoms such as tiredness and dizziness can occur during treatment, Metoject has
minor or moderate influence on the ability to drive and use machines.

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity,
hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-
Johnson syndrome.
Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal
disorders e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite and abnormal liver function
tests e.g. increased ALAT, ASAT, bilirubin, alkaline phosphatase. Other frequently (common) occurring
adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia,
interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema,
erythema and pruritus.
Tabulated list of adverse reactions
The most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal
disorders.
The following headings are used to organise the undesirable effects in order of frequency:
Very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000
to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data)
Infections and infestations
Uncommon: Pharyngitis.
Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis.
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Very rare: Lymphoma (see “description” below).
Blood and lymphatic system disorders
Common: Leukopenia, anaemia, thrombopenia.
Uncommon: Pancytopenia.
Very rare: Agranulocytosis, severe courses of bone marrow depression , lymphoproliferative disorders
(see “description” below).
Not known: Eosinophilia.
Immune system disorders
Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.
Metabolism and nutrition disorders
Uncommon: Precipitation of diabetes mellitus.
Psychiatric disorders
Uncommon: Depression, confusion.

Rare: Mood alterations.
Nervous system disorders
Common: Headache, tiredness, drowsiness.
Uncommon: Dizziness
Very rare: Pain, muscular asthenia or paraesthesia/hypoaesthesia, changes in sense of taste (metallic
taste), convulsions, meningism, acute aseptic meningitis, paralysis.
Not known: Encephalopathy/ leukoencephalopathy.
Eye disorders
Rare: Visual disturbances.
Very rare: Impaired vision, retinopathy.
Cardiac disorders
Rare: Pericarditis, pericardial effusion, pericardial tamponade.
Vascular disorders
Rare: Hypotension, thromboembolic events.
Respiratory, thoracic and mediastinal disorders
Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms
indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of
breath and fever.
Rare: Pulmonary fibrosis, Pneumocystis jirovecii pneumonia, shortness of breath and bronchial asthma,
pleural effusion.
Not known: Epistaxis, pulmonary alveolar haemorrhage.
Gastrointestinal disorders
Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain.
Common: Oral ulcers, diarrhoea.
Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis.
Rare: Gingivitis.
Very rare: Haematemesis, haematorrhea, toxic megacolon.
Hepatobiliary disorders (see section 4.4)
Very common: Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and
bilirubin).
Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.
Rare: Acute hepatitis.
Very rare: Hepatic failure.
Skin and subcutaneous tissue disorders
Common: Exanthema, erythema, pruritus.
Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster,
vasculitis, herpetiform eruptions of the skin, urticaria.
Rare: Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased
pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.
Not known: Skin exfoliation/dermatitis exfoliative

Musculoskeletal and connective tissue disorders
Uncommon: Arthralgia, myalgia, osteoporosis.
Rare: Stress fracture.
Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders).
Renal and urinary disorders
Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.
Rare: Renal failure, oliguria, anuria, electrolyte disturbances.
Not known: Proteinuria
Reproductive system and breast disorders
Uncommon: Inflammation and ulceration of the vagina.
Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal
discharge.
General disorders and administration site conditions
Rare: Fever, wound-healing impairment
Not known: Asthenia, injection site necrosis, oedema.
Description of selected adverse reactions
The appearance and degree of severity of undesirable effects depends on the dosage level and the
frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is
indispensable that patients are monitored regularly by the doctor at short intervals.
Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and
other lymphoproliferative disorders which subsided in a number of cases once treatment with
methotrexate had been discontinued.
Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions (such as
burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain) were observed,
decreasing during therapy.
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 (see details below).
The National Pharmacovigilance & Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

a) Symptoms of overdose
Toxicity of methotrexate mainly affects the haematopoietic system.
b) Treatment measures in the case of overdose

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.
In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of
methotrexate should be administered intravenously or intramuscularly within one hour and dosing
continued until the serum levels of methotrexate are below 10-7 mol/l.
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 dialyser.

Pharmacotherapeutic group: Folic acid analogues,
ATC code: L01BA01
Antirheumatic medicinal product for the treatment of chronic, inflammatory rheumatic diseases and
polyarthritic forms of juvenile idiopathic arthritis. Immunomodulating and anti-inflammatory agent for
the treatment of Crohn’s disease.
Mechanism of action
Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as
antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus
inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the
management of psoriasis, psoriasis arthritis and chronic polyarthritis, is due to an anti-inflammatory or
immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine
concentration at inflamed sites contributes to these effects.
International clinical guidelines reflect the use of methotrexate as a second choice for Crohn’s disease
patients that are intolerant or have failed to respond to first-line immunomodulating agents as
azathioprine (AZA) or 6-mercaptopurine (6 MP).

Absorption
Following oral administration, methotrexate is absorbed from the gastrointestinal tract. In case of lowdosed
administration (dosages between 7.5 mg/m² and 80 mg/m² body surface area), the mean
bioavailability is approx. 70 %, but considerable interindividual and intraindividual deviations are
possible (25 – 100 %). Maximum serum concentrations are achieved after 1 – 2 hours.
Bioavailability of subcutaneous injection is nearly 100 %.
Distribution
Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body
tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in
particular, which can be retained for weeks or months. When administered in small doses, methotrexate
passes into the cerebrospinal fluid in minimal amounts. The terminal half-life is on average 6 – 7 hours
and demonstrates considerable variation (3 – 17 hours). The half-life can be prolonged to 4 times the
normal length in patients who possess a third distribution space (pleural effusion, ascites).

Biotransformation
Approx. 10 % of the administered methotrexate dose is metabolised intrahepatically. The principle
metabolite is 7-hydroxymethotrexate.
Elimination
Excretion takes places, mainly in unchanged form, primarily renal via glomerular filtration and active
secretion in the proximal tubulus.
Approx. 5 – 20 % methotrexate and 1 – 5 % 7-hydroxymethotrexate are eliminated biliary. There is
pronounced enterohepatic circulation.
In the case of renal impairment, elimination is delayed significantly. Impaired elimination with regard to
hepatic impairment is not known.

Animal studies show that methotrexate impairs fertility, is embryo- and foetotoxic and teratogenic.
Methotrexate is mutagenic in vivo and in vitro. As conventional carcinogenicity studies have not been
performed and data from chronic toxicity studies in rodents are inconsistent, methotrexate is considered
not classifiable as to its carcinogenicity to humans.

Sodium chloride
Sodium hydroxide for pH adjustment
Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.

2 years.

Store below 25 °C. Keep the pre-filled syringes in the outer carton in order to protect from light.

Nature of container:
Pre-filled syringes of colourless glass (type I) of 1 ml capacity with embedded injection needle. Plunger
stoppers of chlorobutyl rubber (type I) and polystyrene rods inserted on the stopper to form the syringe
plunger

Pack sizes:
Pre-filled syringes containing 0.20 ml, 0.30 ml, 0.40 ml, 0.50 ml or 0.60 ml solution are available in
packs of 1 syringe with embedded s.c. injection needle.
All pack sizes are available with graduation marks.
Not all pack sizes may be marketed.

The manner of handling and disposal must be consistent with that of other cytotoxic preparations in
accordance with local requirements. Pregnant health care personnel should not handle and/or administer
Metoject.
Methotrexate should not come into contact with the skin or mucosa. In the event of contamination, the
affected area must be rinsed immediately with ample amount of water.
For single use only.
Any unused medicinal product or waste should be disposed of in accordance with local requirements.
Instructions for subcutaneous use
The best places for the injection are:
- upper thighs,
- abdomen except around the navel.
1. Clean the area of and around the chosen injection site.
2. Pull the protective plastic cap straight off.
3. Build a skin fold by gently squeezing the area at the injection site.
4. The fold must be held pinched until the syringe is removed from the skin after the injection.
5. Push the needle fully into the skin at a 90-degree angle.
6. Push the plunger down slowly and inject the liquid underneath the skin. Remove the syringe from the
skin at the same 90-degree angle.