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ZLATAL 20 MG SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE

Active substance(s): METHOTREXATE / METHOTREXATE / METHOTREXATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Zlatal 20 mg solution for injection in pre-filled syringe

2
QUALITATIVE AND QUANTITATIVE
COMPOSITION
1 ml of solution contains 25 mg methotrexate (as methotrexate disodium).
1 pre-filled syringe of 0.8 ml contains 20 mg methotrexate.
Contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially 'sodiumfree'.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for injection in pre-filled syringe.
Clear, yellow solution with a pH of 8.0 - 9.0 and an osmolality of
approximately 300 mOsm/kg

4.1

Therapeutic indications

{Tradename} 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 in adult patients refractory or intolerant to thiopurines.

4.2

Posology and method of administration

Important warning with reference to the dosing of methotrexate:
Methotrexate for the therapy of rheumatic diseases or diseases of the skin must only be used

once weekly. Faulty dosing of methotrexate may lead to serious adverse effects including
fatal course. Please read this paragraph of the SmPC very carefully.

{Tradename} should only be prescribed by physicians with experience in the various
properties of the medicinal product and its mode of action. {Tradename} is injected once
weekly.
It must be explicitly pointed out to the patient that {Tradename} is applied only once a
week.
It is recommended to specify a certain day of the week as “day for injection”.
Posology
Dosage in adult patients with rheumatoid arthritis:
The recommended initial dose is 7.5 mg of methotrexate once weekly, administered either
subcutaneously or intramuscularly. Depending on the individual activity of the disease and
patient tolerability, the initial dose may be increased. A weekly dose of 25 mg should in
general not be exceeded. However, doses exceeding 20 mg/week can be associated with
significant increase in toxicity, especially bone marrow suppression. Response to treatment
can be expected after approximately 4 – 8 weeks. Once the desired therapeutic result has
been achieved, 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)/week. In therapy-refractory
cases the weekly dose may be increased up to 20mg/m² body surface area/week. However,
an increased monitoring frequency is indicated if the dose is increased.
Parenteral administration is limited to subcutaneous and intramuscular injection.
Patients with JIA should always be referred to a rheumatology unit specializing in the
treatment of children/adolescents.
Use in children < 3 years of age is not recommended as insufficient data on efficacy and
safety are available for this population (see section 4.4).
Dosage in patients with psoriasis vulgaris and psoriatic arthritis:
It is recommended that a test dose of 5 - 10 mg be parenterally administered one week prior
to initiation of therapy, in order to detect idiosyncratic adverse effects. The recommended
initial dose is 7.5 mg methotrexate once weekly, administered subcutaneously or
intramuscularly. 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. Once the desired
therapeutic result has been achieved, dose should be reduced gradually to the lowest possible
effective maintenance 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.
Dosage in patients with Crohn's Disease:
• Induction treatment:
25 mg/week administered either subcutaneously or intramuscularly.
Response to treatment can be expected after approximately 8 to 12 weeks.
• Maintenance treatment:
15 mg/week administered either subcutaneously or intramuscularly.
There is not sufficient experience in the paediatric population to recommend {Tradename} for

the treatment of Crohn's Disease in this population.
Patients with renal impairment:
Methotrexate should be used with caution in patients with impaired renal function. The dose
should be adjusted as follows:
Creatinine clearance (ml/min)
> 50
30 – 50
< 30

Dose
100 %
50 %
{Tradename} must not be used

Patients with hepatic impairment:
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)
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).
Duration and method of administration:
The medicinal product is for single use only. {Tradename} can be injected via the
intramuscular or subcutaneous route.
Please also refer to section 6.6. The overall duration of treatment is decided by the doctor.
The solution is to be visually inspected prior to use.
Only clear solutions practically free from particles should be used.
Any contact of methotrexate with skin and mucosa is to be avoided! In case of
contamination, the affected parts are to be rinsed immediately with plenty of water! See
section 6.6.
Methotrexate 25 mg/ml treatment of rheumatoid arthritis, juvenile idiopathic arthritis, severe
psoriasis vulgaris and psoriatic arthritis represents long-term treatment.
Rheumatoid arthritis
Treatment response in patients with rheumatoid arthritis can be expected after 4-8 weeks.
Symptoms may return after treatment discontinuation.
Severe forms of psoriasis vulgaris and psoriatic arthritis
Response to treatment can generally be expected after 2-6 weeks. Depending on the
clinical picture and the changes of laboratory parameters, the therapy is then continued or
discontinued.
Crohn's Disease:
Response to treatment can be expected after approximately 8 to 12 weeks.
Note:
When switching from oral use to parenteral use, a reduction in the dose may be required, due
to the variable bioavailability of methotrexate after oral administration.

Folic acid or folinic acid supplementation may be considered in accordance with current
therapeutic guidelines.

4.3

Contraindications
Zlatal is contraindicated in:

4.4

-

hypersensitivity to the active substanceor to any of the excipients listed in
section 6.1,

-

severe hepatic impairment, if serum if bilirubin is > 5 mg/dl (85.5 µmol/l)
(see also section 4.2),

-

alcohol abuse,

-

severe renal impairment (creatinine clearance less than 20 ml/min., see also
sections 4.2 and 4.4 ),

-

pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia,
thrombocytopenia or significant anaemia,

-

Immunodeficiency,

-

serious, acute or chronic infections such as tuberculosis and HIV,

-

stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer
disease,

-

pregnancy, breast-feeding (see also section 4.6),

-

concurrent vaccination with live vaccines.

Special warnings and precautions for use
Patients must be clearly advised that the therapy is to be administered once a week,
and not every day. Incorrect intake of methotrexate can lead to severe, including
potentially lethal, side effects. Health personnel and patients should be clearly
instructed.
Patients receiving therapy should be appropriately monitored, so that signs of possible
toxic effects or adverse reactions can be recognised and assessed without delay.
Hence, methotrexate should be only administered by, or under the supervision of,
doctors whose knowledge and experience include the use of antimetabolite therapy.
Due to the risk of severe or even fatal toxic reactions, the patients should be
thoroughly informed by the doctor about the risks (including early signs and
symptoms of toxicity) and recommended safety measures. They are to be informed
about the necessity to immediately consult the physician if symptoms of intoxication
occur as well as about the subsequent necessary monitoring of symptoms of
intoxication (including regular laboratory tests).
Doses exceeding 20 mg/week can be associated with significant increase in toxicity,
especially bone marrow suppression.
Methotrexate has been reported to cause impairment of fertility, oligospermia,
menstrual dysfunction and amenorrhoea in humans, during and for a short period
after cessation of therapy. In addition, methotrexate causes embryotoxicity, abortion
and foetal defects in humans. Therefore the possible risks of effects on reproduction

should be discussed with male and female patients of childbearing potential (see
section 4.6). Men treated with methotrexate are recommended not to father a child
during treatment and at least 6 months thereafter. Since treatment with methotrexate
can lead to severe and possibly irreversible disorders in spermatogenesis, men should
seek advice about the possibility of sperm preservation before starting therapy.
Skin and mucosal contacts with methotrexate are to be avoided. In the case of
contamination, the parts concerned should be rinsed with plenty of water.

Recommended examinations and safety measures
Before initiating therapy or upon resuming 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 (in the first two weeks weekly, then every two weeks for the next
month; afterwards, depending on leukocyte count and stability of the patient at least
once monthly during the next six months and at least every three months thereafter):
Increased monitoring frequency should also be considered when increasing the dose.
Particularly elderly patients should be examined for early signs of toxicity in short
intervals.
1. Examination of the oral cavity and throat for mucosal changes.
2. Complete blood count with differential blood count and platelets.
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.
During longer-term therapy with methotrexate bone marrow biopsies are to be
performed.
3. 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.
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 %. Persistent

anomalies of liver-related enzymes and/or decrease in serum albumin may be
indicative for severe hepatotoxicity.
Enzyme diagnostics does not allow any reliable prediction of the development of a
morphologically detectable hepatotoxicity, i.e. even in case of normal transaminases,
hepatic fibrosis only histologically identifiable or, more rarely, also hepatocirrhosis
may be present.
In rheumatological indications, there is no evidence to support use of liver biopsies in
monitoring hepatotoxicity. 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.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.
In the event of a constant increase in liver-related enzymes, consideration should be
given to reducing the dose or discontinuing therapy.
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.
Increased caution should generally be exercised in patients with insulin-dependent
diabetes mellitus, as during methotrexate therapy hepatocirrhosis developed in
isolated cases without intermittent increase in transaminases.
4. Renal function should be monitored via renal function tests and urinanalysis (see
sections 4.2 and 4.3).
If serum creatinine is increased, the dose should be reduced. In serum creatinine
values above 2 mg/dl, no treatment with methotrexate should be done.
As methotrexate is predominantly excreted via the renal route, increased
concentrations can be expected in cases of renal impairment, which may result in
severe adverse reactions.
In cases of possible renal impairment (e.g. in elderly patients), closer monitoring is
required. This
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 disorders. In the presence of risk factors, such as –
even borderline

– impaired renal function, concomitant administration of non-steroidal antiphlogistics
is not recommended. Dehydration may also potentiate the toxicity of methotrexate.
5. Assessment of respiratory system:
Questioning the patient with regard to possible pulmonary dysfunctions, if necessary
lung function test.
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), thoracic pain 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.
Methotrexate should be withdrawn from patients with pulmonary symptoms and a
thorough investigation (including chest x-ray) should be made to exclude infection
and tumours. If methotrexate induced lung disease is suspected treatment with
corticosteroids should be initiated and treatment with methotrexate should not be
restarted.
Pulmonary diseases induced by methotrexate were not always completely reversible
Pulmonary symptoms require a quick diagnosis and discontinuation of methotrexate
therapy. Pulmonary diseases induced by methotrexate, like pneumonitis, can occur
acutely at any time of therapy, were not always completely reversible and have been
reported already at all doses (inclusive low doses of 7.5 mg/week).
During methotrexate therapy, opportunistic infection can occur including
pneumocystis carinii pneumonia, which may take a lethal course. If a patient presents
with pulmonary symptoms, the possibility of pneumocystis carinii pneumonia should
be taken into account.
Special caution is required in patients with impaired pulmonary function.
Particular caution should be exercised in the presence of inactive, chronic infections
(e.g. herpes zoster, tuberculosis, hepatitis B or C), due to possible activation.
6. Methotrexate may, due to its effect on the immune system, impair the response to
vaccinations and interfere with the result of immunological tests.
Concurrent vaccination using live vaccines must not be carried out.
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.

In patients with pathological accumulation of liquid in body cavities (“third space”),
such as ascites or pleural effusions, the plasma elimination half-life of methotrexate is
prolonged.
Pleural effusions and ascites should be drained prior to initiation of methotrexate
treatment.
Conditions leading to dehydration such as emesis, diarrhoea, stomatitis, can increase
the toxicity of methotrexate due to elevated agent levels. In these cases use of
methotrexate should be interrupted until the symptoms cease
It is important to identify patients with possibly elevated methotrexate levels within
48 hours after therapy, as otherwise methotrexate toxicity may be irreversible.
Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of
therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may
occur.
If haematemesis, black discoloration of the stool or blood in stool occur, therapy is to
be interrupted.
Vitamin preparations or other products containing folic acid, folinic acid or their
derivatives may decrease the effectiveness of methotrexate.
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).
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.
This medicinal product contains less than 1 mmol (23 mg) sodium per dose and is i.e.
essentially
“sodium-free“.
The absence of pregnancy should be confirmed before Zlatal is administered.
Methotrexate causes embryotoxicity, abortion and foetal defects in humans.
Methotrexate affects spermatogenesis and oogenesis during the period of its
administration which may result in decreased fertility. These effects appear to be
reversible on discontinuing therapy. Effective contraception in men and women
should be performed during treatment and for at least six months thereafter. The
possible risks of effects on reproduction should be discussed with patients of
childbearing potential and their partners should be advised appropriately (see section
4.6).

4.5
Interaction with other medicinal products and other forms of
interaction
In animal experiments non-steroidal anti-inflammatory drugs (NSAIDs)
including salicylic acid caused reduction of tubular methotrexate secretion
and consequently increased its toxic effects. However, in clinical studies,
where NSAIDs and salicylic acid were given as concomitant medication to
patients with rheumatoid arthritis, no increase of adverse reactions was
observed. Treatment of rheumatoid arthritis with such drugs can be continued
during low-dose methotrexate therapy but only under close medical
supervision.
Regular alcohol consumption and administration of additional hepatotoxic
medicinal products increase the probability of hepatotoxic effects of
methotrexate.
Patients taking potentially hepatotoxic and haematoxic medicinal products
during methotrexate therapy (e.g.
leflunomide, azathioprine, sulphasalazine, and retinoids) should be closely
monitored for possibly increased hepatotoxicity. Alcohol consumption should
be avoided during treatment with Methotrexate 25 mg/ml.
Administration of additional haematotoxic medicinal products (e.g.
metamizole) increase the probability of severe haematoxic effects of
methotrexate.
Be aware of pharmacokinetic interactions between methotrexate,
anticonvulsant drugs (reduced methotrexate blood levels), and 5- fluorouracil
(increased t½ of 5-fluorouracil).
Salicylates, phenylbutazone, phenytoin, barbiturates, tranquillisers, oral
contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides and paminobenzoic acid displace methotrexate from serum albumin binding and
thus increase bioavailability (indirect dose increase).
Probenecid and mild organic acids may also reduce tubular methotrexate
secretion, and thus cause indirect
dose elevations, too.
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.
Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable
broad-spectrum antibiotics may reduce intestinal methotrexate absorption or
interfere with the enterohepatic circulation, due to inhibition of the intestinal
flora or suppression of bacterial metabolism.
Under (pre-)treatment with substances that may have adverse effects on the
bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole,

chloramphenicol, pyrimethamine), the possibility of marked haematopoietic
disorders should be considered.
Co-administration of medications which cause folate deficiency (e.g.
sulphonamides, trimethoprim- sulphamethoxazole) can lead to increased
methotrexate toxicity. Particular caution should therefore also be exercised in
the presence of existing folic acid deficiency.
On the other hand, concomitant administration of folinic acid containing
drugs or of vitamin preparations, which contain folic acid or derivatives, may
impair methotrexate efficacy.
A rise in the toxicity of methotrexate is generally not anticipated when
Methotrexate 25 mg/ml is used concomitantly with other antirheumatic
agents (e.g. gold compounds, penicillamine, hydroxychloroquine,
sulfasalazine, azathioprine, cyclosporin).
Though the combination of methotrexate and sulfasalazine may enhance
methotrexate efficacy by sulfasalazine related inhibition of folic acid
synthesis, and thus may lead to an increased risk of side effects, these were
only observed in single patients within several trials.
Co-administration of proton-pump inhibitors such as omeprazole or
pantoprazole can lead to interactions:
Concomitant administration of methotrexate and omeprazole has led to a
delay in the renal elimination of methotrexate. In combination with
pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate
metabolite, with myalgia and shivering, was reported in one case.
Methotrexate may reduce theophylline clearance. Therefore, theophylline
blood levels should be monitored under concomitant methotrexate
administration.
Excessive consumption of beverages containing caffeine or theophylline
(coffee, soft drinks containing caffeine, black tea) should be avoided during
methotrexate therapy since the efficacy of methotrexate may be reduced due
to possible interaction between methotrexate and methylxanthines at
adenosine receptors.
The combined use of methotrexate and leflunomide may increase the risk for
pancytopenia. Methotrexate leads to increased plasma levels of
mercaptopurines. Therefore, the combination of these may require dose
adjustment.
Particularly in the case of orthopaedic surgery where susceptibility to
infection is high, a combination of methotrexate with immune-modulating
agents must be used with caution.

Anaesthetics on nitric oxide base potentiate the effect of methotrexate on the
folic acid metabolism and lead to severe unpredictable myelosuppression and
stomatitis. This can be reduced by administering calcium folinate.
Colestyramine can increase the non-renal elimination of methotrexate by
interrupting the enterohepatic circulation.
Delayed methotrexate clearance should be considered in combination with
other cytostatic agents. Radiotherapy during use of methotrexate can increase
the risk of soft tissue or bone necrosis
On account of its possible effect on the immune system, methotrexate can
falsify vaccinal and test results
(immunological procedures to record the immune reaction). During
methotrexate therapy concurrent vaccination with live vaccines must not be
carried out (see section 4.3 and 4.4).

4.6

Fertility, Pregnancy and lactation
Pregnancy:
Methotrexate 25 mg/ml is contraindicated during pregnancy (see
section 4.3). In animal studies, methotrexate has shown reproductive
toxicity, especially during the first trimester (see section 5.3).
Methotrexate has been shown to have a teratogenic effect in humans;
it has been reported to cause foetal 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 extremity-related). When methotrexate
was 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 25 mg/ml 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.
Fertility:
As methotrexate can be genotoxic, all women who wish to become
pregnant are advised to consult a genetic councelling centre, if
possible, already prior to therapy, and men should seek advice about
the possibility of sperm preservation before starting therapy.
Breast - feeding:
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 treatment.

4.7

Effects on ability to drive and use machines
CNS symptoms, such as fatigue and confusion, can occur during treatment.
Methotrexate 25 mg/ml has minor or moderate influence on the ability to
drive and use machines.

4.8

Undesirable effects

Occurrence and severity of undesirable effects depend on dose level and frequency of
Methotrexate 25 mg/ml administration. However, as severe adverse reactions may occur
even at lower doses, it is indispensable that the doctor monitors patients regularly at short
intervals.
Most undesirable effects are reversible if recognised early. If such adverse reactions occur,
dose should be reduced or therapy be interrupted and appropriate countermeasures should be
taken (see section 4.9). 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.
Frequencies in this table are defined using the following convention:
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).
Further details are given in the following table. Within each frequency grouping, undesirable
effects are presented in order of decreasing seriousness
The following adverse reactions may occur:
Very
common
Infections
and
infestations

Common

Uncommon

Rare

Very rare/ not
known
Sepsis, infections
(incl. reactivation
inactive chronic
infection) may be
fatal in some case

Cardiac
disorders

Blood and
lymphatic
system
disorders

Pericarditis,
pericardial effusion,
pericardial tamponade

Leukocytopenia
thrombocytopenia,
anaemia

Pancytopenia,
agranulocytosis,
haematopoietic
disorders

Severe courses of
bone marrow
depression, aplas
anaemia.
Lymphadenopath
lymphoproliferati
disorders (partly
reversible),

eosinophilia and
neutropenia.
First signs for these
life-threatening
complications may
be: fever, sore
throat, ulcerations of
oral mucosa, flu-like
complaints, strong
exhaustion, epistaxis
and dermatorrhagia.
Use of methotrexate
should be
interrupted
immediately if the
number of blood
cells significantly
declines

Immune
system
disorders

Allergic reactions,
anaphylactic shock

Metabolism
and
nutrition
disorders

Diabetes mellitus

Psychiatric
disorders
Nervous
system
disorders

Depression,
confusion
Vertigo,
seizures

Headache,
fatigue,
drowsiness

Immunosuppression
Hypogammaglobuli
naemia

Mood fluctuations

Pain, muscular
asthenia or
paresthesia of the
extremities, changes
in sense of taste
(metallic taste),
acute aseptic
meningitis with
meningism
(paralysis,
vomiting),
Not known:
leukoencephalopathy
Severe visual
disturbances

Eye
disorders

13

Insomnia

Conjunctivitis,
retinopathy

Ear and
labyrinth
disorders
Neoplasms
benign,
malignant
and
unspecified
(incl cysts
and polyps)

Individual cases of
lymphoma, which
abated in a number
of cases once
methotrexate
treatment had been
discontinued. In a
recent study, it
was not possible to
establish that
methotrexate
therapy increases
the incidence of
lymphomas

Vascular
disorders

Hypotension,
thromboembolic
events

14

Respiratory,
thoracic and
mediastinal
disorders

Gastrointest
i nal
disorders

Pulmonary
Pulmonary fibrosis Pharyngitis, apnoea,
complications
bronchial asthma-like
due to
reactions with cough,
interstitial
dyspnoe and
alveolitis/pneu
pathological findings
monitis and
in the lung function
test
related deaths
(independent of
dose and
duration of
methotrexate
treatment).
Typical
symptoms may
be: general
illness; dry,
irritating
cough;
shortness of
breath
progressing to
rest dyspnoea,
chest pain,
fever.

Loss of
appetite,
nausea,
vomiting,
abdominal
pain,
inflammatio
n and
ulcerations
of the

Diarrhoea
(especially
during the first
24-48 hours
after
administration
of
Methotrexate
25 mg/ml).

Gastrointestinal
ulcers and
bleeding.

15

Enteritis, melaena
Gingivitis,
malabsorption

Pneumocystis
carinii pneumonia
and
other pulmonary
infections, ,
chronic obstructive
pulmonary disease.
Pleural effusion

Haematemesis, toxic
megacolon

mucous
membrane
of mouth
and throat
(especially
during the
first 24-48
hours after
administrati
on of
Methotrexat
e 25
mg/ml).
Stomatitis,
dyspepsia

Hepatobiliary
disorders

Increase in
liver-related
enzymes
(ALAT
[GPT],
ASAT
[GOT],
alkaline
phosphatase
and
bilirubin).

Development of
liver fattening,
fibrosis and
cirrhosis (occurs
frequently despite
regularly
monitored, normal
values of liver
enzymes); drop of
serum albumin.

14

Acute hepatitis

Hepatic failure

Skin and
subcutaneou
s tissue
disorders

Exanthema,
erythema,
itching

Urticaria,
photosensibility,
enhanced
pigmentation of
the skin,
hair loss,
increase of
rheumatic nodules,
herpes zoster,
painful lesions of
psoriatic plaque
(Psoriatic lesions
can exacerbate due
to UV radiation
during
concomitant
treatment with
methotrexate (also
see section 4.4);
severe toxic
reactions:
vasculitis,
herpetiform
eruption of the
skin,
Stevens-Johnson
syndrome,

15

Increased pigmentary
changes of nails,
onycholysis,
acne,
petechiae,
ecchymoses,
erythema multiforme,
cutaneous
erythematous
eruptions.

acute paronychia,
furunculosis,
telangiectasia
hidradenitis

toxic epidermal
necrolysis (Lyell’s
syndrome).

Musculoske
l etal
system,
connective
tissue and
bone
disorders

Arthralgia,
myalgia,
osteoporosis

Stress fracture

Renal and
urinary
disorders

Inflammation and
ulceration of the
urinary bladder
(possibly with
haematuria),
dysuria.

Renal failure, oliguria, Proteinuria
anuria, azotaemia

General
disorders
and
administrati
on site
conditions

After
intramuscular use
of methotrexate,
local adverse
reactions (burning
sensation) or
damage (sterile
formation of
abscess,
destruction of fatty
tissue) can occur
at the site of
injection, disturbed
wound healing.

Fever, Subcutaneo
administration of
methotrexate sho
good local
tolerance. Only m
local skin reaction
the
number of which
decreased in the
course of treatmen
have been observe
so far.

Investigatio
ns
Reproductiv
e system
and breast
disorders

Inflammation and
ulceration of the
vagina

Oligospermia,
menstruation
disorders

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.
When methotrexate is given by the intramuscular route, local undesirable effects (burning

16

Loss of libido,
impotence, , vagin
discharge, infertil
gynaecomastia

sensation) or damage (formation of sterile abscess, destruction of fatty tissue) at the site of
injection can occur commonly. Subcutaneous application of methotrexate is locally well
tolerated. Only mild local skin reactions 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 the national
reporting system listed in Appendix V*.

4.9

Overdose
a) Symptoms of overdose
The adverse toxic effects of methotrexate mainly affect the haematopoietic
and gastrointestinal system. Symptoms include leukocytopenia,
thrombocytopenia, anaemia, pancytopenia, neutropenia, bone marrow
depression, mucositis, stomatitis, oral ulceration, nausea, vomiting,
gastrointestinal ulceration and gastrointestinal bleeding. Some patients
showed no signs of overdose.
There are reports of death due to sepsis, septic shock, renal failure and
aplastic anaemia.
b ) Treatment of overdose
Calcium folinate is the specific antidote for neutralising the adverse toxic
effects of methotrexate. In the event 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 1 hour, and
dosing continued until serum levels of methotrexate are below 10-7 mol/L.
In the event of a massive overdose, hydration and urinary alkalisation may
be required to prevent precipitation of methotrexate and/or its metabolites
within the renal tubules. Neither haemodialysis nor peritoneal dialysis has
been shown to improve methotrexate elimination. Effective methotrexate
clearance has been reported with acute, intermittent haemodialysis using a
high-flux dialyser.
In patients with rheumatoid arthritis, polyarticular juvenile idiopathic
arthritis, psoriasis arthritis or psoriasis vulgaris, administration of folic or
folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms,
inflammation of oral mucosa, hair loss and increase of liver enzymes), see
section 4.5. Prior to using folic acid products, monitoring of vitamin B12
levels is recommended, since folic acid may mask an existing vitamin B12
deficiency, particularly in adults over 50 years of age.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

17

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, other
immunosuppressants. ATC-code: L04AX03
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.

5.2

Pharmacokinetic properties
Absorption
After oral application, methotrexate is absorbed from the gastrointestinal
tract. When administered in low doses (7.5mg/m2 to 80mg/m2 body surface
area), methotrexate has a mean bioavailability of approximately 70%,
although considerable inter- and intra-subject variations are possible (25100%). Plasma peak concentrations are attained within 1-2 hours.
Subcutaneous, intravenous and intramuscular administration demonstrated
similar bioavailability.

Distribution
Approximately 50% of methotrexate is bound to serum proteins. Upon
being distributed into body tissues, high concentrations particularly in liver,
kidneys and spleen in form of polyglutamates can be found, which can be
retained for weeks or months. When administered in small doses,
methotrexate passes into the liquor in minimal amounts; under high doses
(300mg/kg body weight), concentrations between 4 and 7 µg/ml have been
measured in the liquor. Average terminal half-life is 6-7 hours and
demonstrates considerable variation (3-17 hours). Half-life may be
prolonged to 4 times the
normal length in patients with third spaces (pleural effusion, ascites).
Biotransformation
Approximately 10% of the administered methotrexate is metabolised
intrahepatically. The major metabolite is 7-hydroxymethotrexate.
Elimination
Excretion takes place, mainly in unchanged form, primarily renal via
glomerular filtration and active secretion in the proximal tubulus. Approx.
5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are eliminated
via the bile. Pronounced enterohepatic blood flow exists.
In case of renal insufficiency, elimination is delayed significantly. Impaired
elimination in presence of hepatic insufficiency is not known.
Methotrexate passes the placental barrier in rats and monkeys.

18

5.3

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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium chloride
Sodium hydroxide (for pH adjustment)
Water for injections

6.2

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

6.3

Shelf life
24 months

6.4

Special precautions for storage
Store below 25°C.
Keep the syringe in the outer carton in order to protect from light.
Do not freeze.

6.5

Nature and contents of container

19

Nature of container:
Pre-filled syringes of colourless glass (type I) of 1 ml capacity with attached injection
needle and with a safety device to prevent needlestick injury and re-use. Plunger
stoppers of chlorobutyl rubber.
Pack sizes:
Pre-filled syringes containing 7.5 mg (in 0.3 ml), 10 mg (in 0.4 ml), 12.5 mg (in 0.5
ml), 15 mg (in 0.6 ml), 17.5 mg (in 0.7 ml), 20 mg (in 0.8 ml), 22.5 mg (in 0.9 ml)
and 25 mg (1.0 ml) methotrexate in solution for injection in packs of 1, 4, 6 and 24.
Packs of 1, 4, 6 and 24 pre-filled syringes contain 2, 8, 12 and 48 alcohol swabs,
respectively.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
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 methotrexate 25 mg/ml.
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 solution should be discarded.
Any unused product or waste material should be disposed of in accordance with local
requirements for cytotoxic agents.

7

MARKETING AUTHORISATION HOLDER
Nordic Group B.V.
Siriusdreef 22
2132WT Hoofddorp
The Netherlands

8

MARKETING AUTHORISATION NUMBER(S)
PL 40621/0017

20

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
05/02/2015

10

DATE OF REVISION OF THE TEXT
19/06/2017

21

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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