Methotrexate 2.

5 mg T ablets SMPC, Taj Phar mace uticals

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RX Adults and Children:

Methotrexate may be given by oral,
METHOTREXATE intramuscular, intravenous (bolus injection or
TABLETS USP infusion), intrathecal and intra-arterial routes of
administration. Dosages are based on the
2.5 MG patient's body weight or surface area except in
the case of intrathecal administration when a
1.NAME OF THE MEDICINAL maximum dose of 15 mg is recommended.
PRODUCT Doses should be reduced in cases of
haematological deficiency and hepatic or renal
Methotrexate 2.5 mg Tablets impairment. Larger doses (greater than 100 mg)
2. QUALITATIVE AND are usually given by intravenous infusion over
periods not exceeding 24 hours. Part of the dose
QUANTITATIVE COMPOSITION
may be given in an initial rapid intravenous
Each tablet contains methotrexate sodium injection.
equivalent to 2.5 mg of methotrexate.
Methotrexate has been used with beneficial
Excipient(s) with known effect effects in a wide variety of neoplastic diseases,
alone and in combination with other cytotoxic
Lactose monohydrate- 66.166 mg per tablet agents, hormones, radiotherapy or surgery.
For the full list of excipients, see section 6.1. Dosage schedules therefore vary considerably,
depending on the clinical use, particularly when
3. PHARMACEUTICAL FORM intermittent high-dose regimes are followed by
Tablet the administration of Calcium Leucovorin
(calcium folinate) to rescue normal cells from
Round, biconvex, yellow tablets. toxic effects.
4. CLINICAL PARTICULARS Examples of doses of methotrexate that have
been used for particular indications are given
4.1 Therapeutic indications
below
Methotrexate is a folic acid antagonist and is
classified as an antimetabolite cytotoxic agent. Choriocarcinoma and other trophoblastic
tumours: Non-metastatic gestational
Methotrexate has been used to produce
trophoblastic neoplasms have been treated
regression in a wide range of neoplastic
successfully with 0.25-1 mg /kg up to a
conditions including acute leukaemias, non-
maximum of 60 mg intramuscularly every 48
Hodgkin's lymphoma, soft-tissue and osteogenic
hours for four doses, followed by Calcium
sarcomas, and solid tumours particularly breast,
Leucovorin rescue. This course of treatment is
lung, head and neck, bladder, cervical, ovarian,
and testicular carcinoma. repeated at seven day intervals until levels of
urinary chorionic gonadotrophin hormone return
The treatment of neoplastic disease. to normal. Not less than four courses of
Methotrexate has also been used in the treatment treatment are usually necessary. Patients with
of severe cases of uncontrolled psoriasis, complications, such as extensive metastases,
unresponsive to conventional therapy. may be treated with methotrexate in
combination with other cytotoxic drugs.
It is also used in the treatment of adults with
severe, active, classical or definite rheumatoid Methotrexate has also been used in similar doses
arthritis who are unresponsive or intolerant to for the treatment of hydatidiform mole and
conventional therapy. chorio-adenoma destruens.
4.2 Posology and method of administration Leukaemia in children: In acute lymphocytic
leukaemia remissions are usually best induced
Posology
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with a combination of corticosteroids and other intravenous infusions of 20-300 mg/kg

cytotoxic agents. (approximately 600-9,000 mg/m2) of
methotrexate followed by Calcium Leucovorin
Methotrexate 15 mg/m2, given parenterally or rescue. Methotrexate has also been used as the
orally once weekly, in combination with other sole treatment in metastatic cases of osteogenic
drugs appears to be the treatment of choice for sarcoma.
maintenance of drug-induced remissions.
Bronchogenic carcinoma: Intravenous
Meningeal leukaemia in children: Doses up to infusions of 20-100 mg/m2 of methotrexate have
15 mg, intrathecally, at weekly intervals, until
been included in cyclical combination regimes
the CSF appears normal (usually two to three
for the treatment of advanced tumours. High
weeks), have been found useful for the treatment doses with Calcium Leucovorin Rescue have
of meningeal leukaemia.
also been employed as the sole treatment.
Although intravenous doses of the order of 50 Head and neck cancer: Intravenous infusions of
mg/m2 of methotrexate do not appreciably 240-1,080 mg/m2 with Calcium Leucovorin
penetrate the CSF, larger doses of the order of rescue have been used both as pre-operative
500 mg/ m2 or greater do produce cytotoxic
levels of methotrexate in the CSF. This type of
Important warning about the dosage of Methotrexate
therapy has been used in short courses, followed 2.5 mg Tablets (methotrexate)
by administration of Calcium Leucovorin, as In the treatment of psoriasis and rheumatoid arthritis,
initial maintenance therapy to prevent leukaemic Methotrexate 2.5 mg Tablets (methotrexate) must only
invasion of the central nervous system in be taken once a week. Dosage errors in the use of
children with poor prognosis lymphocytic Methotrexate 2.5 mg Tablets (methotrexate) can result in
leukaemia. serious adverse reactions, including death.
Please read this section of the summary of product
Lymphoma: Non- Hodgkin's lymphoma, e.g. characteristics very carefully.
childhood lymphosarcoma has recently been adjuvant therapy and in the treatment of
treated with 3-30 mg/kg (approximately 90-900 advanced tumours. Intra-arterial infusions of
mg/m2) of methotrexate given by intravenous methotrexate have been used in the treatment of
injection and infusion followed by head and neck cancers.
administration of Calcium Leucovorin with the
higher doses. Some cases of Burkitt's Bladder carcinoma: Intravenous injections or
lymphoma, when treated in the early stages with infusions of methotrexate in doses up to 100 mg
courses of 15 mg/m2 daily orally for five days, every one or two weeks have been used in the
have shown prolonged remissions. Combination treatment of bladder carcinoma with promising
chemotherapy is also commonly used in all results, varying from only symptomatic relief to
stages of the disease. complete though unsustained regressions. The
use of high doses of methotrexate with Calcium
Breast cancer: Methotrexate, in intravenous Leucovorin Rescue is currently being evaluated.
doses of 10-60 mg/m2, is commonly included in
cyclical combination regimes with other Psoriasis: It is recommended that a test dose of
cytotoxic drugs in the treatment of advanced 5-10 mg should be administered, one week prior
breast cancer. Similar regimes have also been to therapy to detect idiosyncratic adverse
used as adjuvant therapy in early cases following reactions.
mastectomy and/or radiotherapy. In most cases of severe uncontrolled psoriasis,
Osteogenic sarcoma: The use of methotrexate unresponsive to conventional therapy, 10-25 mg
alone and in cyclical combination regimes has orally once a week and adjusted by the patient's
recently been introduced as an adjuvant therapy response is recommended. The prescriber should
to the primary treatment of osteogenic sarcoma specify the day of intake on the prescription.
by amputation with or without prosthetic bone
replacement. This has involved the use of
Methotrexate 2.5 mg T ablets SMPC, Taj Phar mace uticals
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The use of methotrexate in psoriasis may permit • Pre-existing blood dyscrasias, such as bone
the return to conventional topical therapy which marrow hypoplasia, significant anaemia,
should be encouraged. leucopenia, or thrombocytopenia
Rheumatoid arthritis: It is recommended that a • Alcoholism
test dose of 5-10 mg should be administered, one
week prior to therapy to detect idiosyncratic • Severe acute or chronic infections and
adverse reactions. immunodeficiency syndrome

In adults with severe, acute, classical or definite • Methotrexate is teratogenic and should not be
rheumatoid arthritis who are unresponsive or given during pregnancy or to mothers who are
breast-feeding (see section 4.6)
intolerant to conventional therapy, 7.5 mg orally
once weekly or divided oral doses of 2.5 mg at • During methotrexate therapy concurrent
12 hour intervals for 3 doses (7.5 mg) as a vaccination with live vaccines must not be
course once weekly. The schedule may be carried out
adjusted gradually to achieve an optimal
response but should not exceed a total weekly • Methotrexate tablets should not be used
dose of 20 mg. Once response has been concomitantly with drugs with antifolate
achieved, the schedule should be reduced to the properties (see section 4.5)
lowest possible effective dose. The prescriber • Following administration to a man or woman
should specify the day of intake on the conception should be avoided by using an
prescription effective contraceptive method for at least 6
Elderly: months after using Methotrexate 2.5 mg tablets
(see Section 4.4).
Due to diminished hepatic and renal function
and decreased folate stores, methotrexate should • Breast-feeding (see section 4.6)
be used with extreme caution in elderly patients, Additionally, for non-oncological indications
a reduction in dosage should be considered and
these patients should be closely monitored for • Pregnancy (see section 4.6)
early signs of toxicity.
4.4 Special Warnings and precautions for
Children: use
Safety and effectiveness in children have not WARNINGS
been established, other than in cancer
chemotherapy. The prescriber should specify the day of intake
on the prescription.
Method of Administration: Oral.
The prescriber should make sure patients
4.3 Contraindications understand that Methotrexate 2.5 mg Tablets
Methotrexate is contra-indicated in the presence (methotrexate) should only be taken once a
of: week.
• Hypersensitivity to the active substance or to Patients should be instructed on the importance
any of the excipients listed in section 6.1 of adhering to the once- weekly intakes.
• Significantly impaired hepatic function Methotrexate must be used only by physicians
experienced in antimetabolite Chemotherapy.
• Severe/significantly impaired renal function
Because of the possibility of fatal or severe
• Liver disease including fibrosis, cirrhosis, toxicity, the physician should fully inform the
recent or active hepatitis patient of the risks involved and provide close
• Active infectious disease medical supervision.
Methotrexate 2.5 mg T ablets SMPC, Taj Phar mace uticals
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Monitoring (prior to starting treatment) – see responsive to other forms of therapy, and only
also below when the diagnosis has been established by
biopsy and/or after dermatological consultation
Before beginning or reinstituting methotrexate (see also sections 4.1 and 4.2)
after a rest period, the patient's renal, liver and
bone marrow function should be assessed by • The patient should be clearly informed that, in
history, physical examination and laboratory cases of psoriasis, methotrexate is taken once
tests. A chest X-ray should also be taken (see weekly. The prescriber should specify the day of
Respiratory effects below). intake on the prescription. Patients should be
aware of the importance of adhering to once
Monitoring (during and after treatment) – see
weekly intakes which is that daily/more frequent
also below
administration can result in severe toxicity
• During treatment patients should be • In longer-term treatment liver biopsies should
appropriately supervised so that toxic signs or be performed (see Hepatotoxicity below).
symptoms, or adverse reactions may be detected
and evaluated with minimal delay Use in rheumatoid arthritis (RA)
• Full blood count (including haematocrit), • The patient should be clearly informed that, in
hepatic and renal function tests (including cases of RA, methotrexate is taken once weekly.
urinalysis) should be carried out every week The prescriber should specify the day of intake
until treatment is stabilized, thereafter every 2 to on the prescription. Patients should be aware of
3 months throughout treatment. This will include the importance of adhering to once weekly
a routine examination of lymph nodes and intakes which is that daily/more frequent
patients should report any unusual swelling to administration can result in severe toxicity
the doctor
• When to perform a liver biopsy in
• More frequent check-ups be necessary when rheumatological indications (cumulative
dose/duration of therapy) has not been clearly
- the dose is increased
established (see also below).
- there is an increased risk of raised Lung manifestations of RA and other connective
methotrexate blood levels (e.g. dehydration, tissue disorders are recognised to occur. In
impaired renal function, additional or increased
patients with RA, the physician should be
dose of medicines, such as NSAIDs, specifically alerted to the potential for
administered concomitantly (see below &
methotrexate induced adverse effects on the
section 4.5) pulmonary system.
• Haematopoietic suppression is common and Other warnings/precautions
may occur without warning when a patient is on
an apparently “safe” dose, so full blood counts • Pleural effusions and ascites should be drained
should be closely monitored during and after before methotrexate is started. Methotrexate can
treatment. If any clinically significant drop in accumulate in these fluids and may be re-
blood cell count occurs, methotrexate should be excreted into the circulation, prolonging the
stopped immediately and appropriate therapy serum half-life and resulting in unexpected
instituted. Patients should be advised to report toxicity (e.g. myelosuppression – see below)
all signs and symptoms suggestive of infection
or of a blood dyscrasia. • Methotrexate should be used with extreme
caution in
Use in psoriasis
- debility
• Deaths have been reported associated with the
- extreme youth (see section 4.2)
use of methotrexate in psoriasis, so its use
should be restricted to severe recalcitrant, - old age (see section 4.2)
disabling disease which is not adequately
Methotrexate 2.5 mg T ablets SMPC, Taj Phar mace uticals
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- psychiatric disorders - History of alcohol abuse

• Adequate hydration prior to and during - History of liver disease including hepatitis B or
treatment is required to limit the risk of renal C
toxicity (see below)
- Family history of hereditary hepatopathy
• Folate deficiency may increase methotrexate
toxicity • Other factors that may indicate an increased
risk include
• Systemic toxicity may follow intrathecal use
(appropriate monitoring required) - Diabetes mellitus
- Adiposity
• Tumour lysis syndrome may occur in patients
with rapidly growing tumours - History of exposure to hepatotoxic medicines
or chemicals.
• If acute methotrexate toxicity occurs patients
may require folinic acid (to neutralise bone Liver biopsies
marrow effects). Plasma methotrexate levels
should be monitored in order to calculate the • Liver biopsies should be considered after
appropriate dose cumulative doses > 1.0 to 1.5g, if hepatic
impairment is suspected
• Patients should report all symptoms and signs
suggestive of infection, especially sore throat. • In patients with risk factors (see above), liver
biopsy is recommended during or shortly after
Hepatotoxicity starting methotrexate. Since a small percentage
• Methotrexate is hepatotoxic, particularly at of patients discontinue therapy for various
high doses or with prolonged therapy. Liver reasons after 2-4 months, the first biopsy can be
delayed to a time after this initial phase (i.e.
atrophy, necrosis, cirrhosis, fatty changes, and
when longer-term therapy is proposed)
periportal fibrosis have been reported. Changes
may occur without prior signs of toxicity, so it is • In low risk patients with RA, there is no robust
imperative that hepatic function be determined evidence to support use of a liver biopsy to
before treatment is started and monitored monitor hepatic toxicity (see above)
regularly throughout therapy (see above)
• In case of longer-term treatment of psoriasis
• Temporary increases in transaminases to twice with methotrexate, liver biopsies should be
or three times of the upper limit of normal have performed.
been reported by patients at a frequency of 13 -
20 %, however methotrexate should not be Haematological effects (myelosuppression)
started or should be discontinued if there are any • Methotrexate can suppress haematopoiesis.
clinically relevant abnormalities of liver function This can occur abruptly and with apparently
tests or liver biopsy. If such abnormalities return “safe” doses. Monitoring is therefore required
to normal within two weeks, the physician may (see above)
consider it appropriate to re-start methotrexate
• In patients with malignant disease (with
• Additional hepatotoxic drugs should not be existing bone marrow aplasia, leucopenia,
taken during treatment with methotrexate unless thrombocytopenia, and/or anaemia)
clearly necessary and the consumption of methotrexate should be used with considerable
alcohol should be avoided or greatly reduced caution, if at all
(see below and section 4.5)
• If there are clinically significant falls in white
• Risk factors for the development of cell or platelet counts, methotrexate should be
hepatotoxicity primarily include stopped immediately.
- Daily (rather than weekly) dosing Respiratory effects
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• A chest X-ray is recommended prior to • In renal impairment the dose of methotrexate

initiation of methotrexate therapy as acute or should be reduced. High doses may cause
chronic interstitial pneumonitis, often associated precipitation of it or its metabolites in the renal
with blood eosinophilia may occur. Deaths have tubules. A high fluid throughput and
been reported. Typically symptoms include alkalinisation of the urine to pH 6.5-7.0 by oral
dyspnoea, cough (especially a dry, non- or intravenous administration of sodium
productive cough), and fever. Patients with RA bicarbonate (5 x 625 mg tablets every three
are particularly at risk hours) or acetazolamide 500 mg orally four
times a day) is recommended as a preventive
• Patients should be informed of the risk, measure
monitored for relevant symptoms at every visit
and advised to contact their doctor immediately • Monitoring of serum methotrexate levels are
should they develop persistent cough or recommended.
dyspnoea
Gastro-intestinal effects
• Methotrexate should be withdrawn from
patients with pulmonary symptoms and a • Diarrhoea and ulcerative stomatitis are
frequent toxic effects and require interruption of
thorough investigation undertaken to exclude
infection as potentially fatal opportunistic therapy, otherwise haemorrhagic enteritis and
death from intestinal perforation may occur
infections (including Pneumocystis carnii) may
occur. Reversible eosinophilic pulmonary • Extreme caution should be exercised if there is
reactions may occur, particularly after long-term peptic ulcer or ulcerative colitis.
treatment
Effects on fertility and reproduction (pregnancy
• If methotrexate induced lung disease is & breast-feeding) - see also sections 4.3 and 4.6
suspected treatment with corticosteroids should
be initiated and treatment with methotrexate • Methotrexate affects gametogenesis and may
should not be restarted result in decreased fertility which is thought to
be reversible on discontinuation of therapy
• If interstitial fibrosis develops it may be
treatment-resistant. • It may impair menstrual function with
consequent amenorrhoea, during and for a short
• In addition, pulmonary alveolar haemorrhage period after therapy has stopped
has been reported with methotrexate used in
rheumatologic and related indications. This • It causes embryotoxicity, abortion and foetal
event may also be associated with vasculitis and death and/or congenital anomalies in humans. It
other comorbidities. Prompt investigations is therefore contraindicated in pregnancy. An
should be considered when pulmonary alveolar existing pregnancy should be excluded with
haemorrhage is suspected to confirm the certainty before starting methotrexate
diagnosis. • If this drug is used during pregnancy for
Renal effects antineoplastic indications, or if the patient
becomes pregnant while taking this drug, the
• Methotrexate is excreted primarily by the patient should be appraised of the potential
kidneys. Its use in patients with renal hazard to the foetus
impairment should only be undertaken with
extreme caution. Renal function should be • Following administration to man or woman
closely monitored before, during and after conception should be avoided by using an
treatment. Caution should be exercised if there is effective contraceptive method for at least 6
significant renal impairment as its use may result months after stopping methotrexate. (see section
in accumulation/toxicity with additional renal 4.3)
damage. Renal lesions may develop if the • Methotrexate passes into breast milk with
urinary flow is impeded and urinary pH is low, consequent toxicity to the baby. Breast feeding
especially if large doses have been administered is contraindicated during lactation.
Methotrexate 2.5 mg T ablets SMPC, Taj Phar mace uticals
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Immunosuppressive activity doses) and nonsteroidal anti-inflammatory drugs

(NSAIDs)
• The immunosuppressive effect of methotrexate
should be taken into account when immune • In the treatment of rheumatoid arthritis,
responses of patients are important or essential. treatment with acetylsalicylic acid and NSAIDs
Special attention should be paid in cases of as well as small-dose steroids can be continued,
inactive chronic infections (e.g. herpes zoster, but the possible increased risk of toxicity needs
tuberculosis, hepatitis B or C) because of their to be borne in mind. The steroid dose can be
potential activation reduced gradually in patients who exhibit
therapeutic response to methotrexate
• Extreme caution is required in the presence of
acute infection. If infection occurs or becomes a • Interaction between methotrexate and other
threat during methotrexate use, it should be antirheumatic agents, such as gold,
stopped. Appropriate antibiotic therapy is penicillamine, hydroxychloroquine,
usually indicated sulphasalazine or other cytotoxic agents, have
not been studied comprehensively but co-
• Responses to concurrent vaccination may be administration may involve an increased
decreased. Vaccination with live vaccines are frequency of adverse reactions.
contraindicated during methotrexate therapy as
severe antigenic reactions may occur (see Folate antagonists
section 4.3).
Concomitant administration of folate antagonists
Development of malignant lymphomas such as trimethoprim/sulphamethoxazole has
been reported to cause an acute megaloblastic
Malignant lymphomas may occur in patients pancytopenia in rare instances.
receiving low dose methotrexate, in which case
therapy must be discontinued. Failure of the Vitamin preparations
lymphoma to show signs of spontaneous
regression requires the initiation of cytotoxic If these contain folic acid (or its derivatives)
they may alter the response to Methotrexate.
therapy.
Other hepatoxic/haematotoxic drugs
Serious skin reactions
Severe (occasionally fatal) skin reactions such as Closer monitoring of liver enzymes and/or blood
Stevens-Johnson syndrome, toxic epidermal counts should be exercised in patients taking
necrolysis and erythema multiforme have been other hepatotoxic and/or haematotoxic
medicines concomitantly.
reported within a few days of a single or
multiple doses of methotrexate. Binding to albumin
Concurrent medication (see also section 4.5) Methotrexate is part-bound to serum albumin
DMARDs (disease-modifying antirheumatic and toxicity may be increased because of
drugs) displacement by certain drugs such as
salicylates, sulphonamides, phenytoin, and some
Concomitant administration of hepatotoxic or antibacterials such as tetracycline,
haematotoxic DMARDs (e.g. leflunomide) is not chloramphenicol and para-aminobenzoic acid.
advisable. Due to the possibility of fatal or These drugs, especially salicylates and
severe toxic reactions, the patient should be fully sulphonamides, whether antibacterial,
informed by the physician of the risks involved hypoglycaemic or diuretic, should not be given
and be under constant supervision. concurrently until the significance of these
findings is established.
NSAIDs
Concomitant other therapies (radiotherapy:
• Serious adverse reactions including deaths ultraviolet radiation/PUVA)
have been reported with concomitant
administration of methotrexate (usually in high
Methotrexate 2.5 mg T ablets SMPC, Taj Phar mace uticals
METHOT REX ATE Taj Phar ma : U ses, Side E ffe cts, Intera ctions , Picture s, Warni ngs, METH OTRE XATE Dosage & Rx Info | METH OTRE XATE Uses , Side Effects -: Indications, Side E ffe cts, War nings, ME THOT REX ATE - Dr ug Informati on - Taj P harma, M ETHOT REXATE dose Taj pharma ceuti cals METH OTRE XATE interactions, Taj Phar mace utical METH OTRE XATE contraindications, METH OT REXATE price, METH OTREXATE Taj P harma M ethotrexate 2 .5 mg T ablets. SMPC- Taj Phar ma . Stay connecte d to all updated on METHOT REXATE Taj P harma ceutical s Taj phar mace uticals Hyderabad.

• Methotrexate used concurrently with General anaesthesia – nitrous oxide increases the
radiotherapy may increase the risk of soft tissue antifolate effect of methotrexate (increased
necrosis and osteonecrosis frequency of stomatitis).
• Psoriatic lesions may get worse if methotrexate Antipsychotics – increased risk of
is combined with ultraviolet radiation/PUVA. agranulocytosis with olanzapine.
Lactose intolerance Retinoids – plasma concentrations of
methotrexate increased by acitretin – also
The tablets contain lactose monohydrate. increased risk of hepatotoxicity.
Patients with rare hereditary problems of
galactose intolerance, total lactase deficiency or Azopropazone – excretion of methotrexate
glucose-galactose malabsorption should not take reduced.
this medicine.
NSAIDs (see also below) should not be
Fertility administered before or concurrently with high-
dose methotrexate - increased and prolonged
Methotrexate has been reported to cause serum methotrexate concentrations with
impairment of fertility, oligospermia, menstrual consequent increased gastrointestinal and
dysfunction and amenorrhoea in humans during haematological toxicity. Methotrexate dosage
and for a short period after the discontinuation
should be monitored if concomitant treatment
of treatment, affecting spermatogenesis and with aspirin, ibuprofen or indometacin
oogenesis during the period of its administration (NSAIDs) is commenced, as concomitant use of
- effects that appear to be reversible on NSAID's has been associated with fatal
discontinuing therapy. methotrexate toxicity.
Teratogenicity – Reproductive risk Other hepato- , myelo- or nephrotoxic drugs
Methotrexate causes embryotoxicity, abortion Sulfamethoxazole and folate antagonists such as
and foetal malformations in humans. Therefore, trimethoprim (as co-trimoxazole) – increased
the possible effects on reproduction, pregnancy risk of haematological toxicity.
loss and congenital malformations should be
discussed with female patients of childbearing Considerable caution required
age (see section 4.6). In non-oncologic
indications, the absence of pregnancy must be Probenecid & weak organic acids (e.g. loop
confirmed before Methotrexate 2.5 mg Tablets is diuretics: pyrazoles) - excretion of methotrexate
reduced (increased risk of toxicity).
used. If women of a sexually mature age are
treated, effective contraception must be used Caution required
during treatment and for at least six months
after. Analgesics

For contraception advice for men see section • NSAIDs (see also above) – In animals low
4.6. doses of methotrexate with NSAIDs have been
found to decrease the tubular secretion of
4.5 Interaction with other medicinal methotrexate and possibly to increase its
products and other forms of interaction toxicity. However patients with rheumatoid
arthritis (or psoriasis) have been treated
Concurrent use contra-indicated concurrently with methotrexate 7.5 - 15
Methotrexate is immunosuppressive and may mg/week without significant problems
therefore reduce immunological response to • Aspirin and other salicylates - possible
concurrent vaccination. Severe antigenic alteration of the pharmacokinetics of
reactions may occur if a live vaccine is given methotrexate/increased risk of toxicity.
concurrently (see sections 4.3 and 4.4).
Antibacterials
Avoid concomitant use
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• Neomycin (and possibly tetracycline, Methotrexate possibly increases plasma

chloramphenicol: non-absorbable broad concentrations of theophylline.
spectrum antibiotics) – reduced absorption of
methotrexate Ulcer-healing drugs – proton pump inhibitors

• Ciprofloxacin – excretion of methotrexate Omeprazole and pantoprazole – excretion of

possibly reduced (increased risk of toxicity) methotrexate possibly reduced (increased risk of
toxicity).
• Doxycycline, sulphonamides, tetracyclines -
increased risk of methotrexate toxicity Vitamin preparations

• Penicillin – reduced excretion of methotrexate Vitamin preparations containing folic acid or its
- increased risk of toxicity (hematological and derivatives may change response to
gastrointestinal). methotrexate.

Antiepileptics Potassium – sparing diuretics

• Antifolate effect of methotrexate increased by Triamterene - bone marrow suppression and

phenytoin reduced folate concentrations have been reported
when triamterene and methotrexate were co-
• Phenytoin – absorption possible decreased by administered.
cytotoxics (risk of exacerbation of convulsions)
Other possible interactions
• Enzyme-inducing antiepileptics –
increased/altered metabolism and/or clearance of Oral hypoglycaemics – possible reduced
methotrexate methotrexate excretion.

• Carbamazepine, phenytoin and valproate Thiazide diuretics – possible reduced

methotrexate excretion.
serum levels can be reduced by antineoplastic
drugs with seizures if the antiepileptic doses are The concurrent administration of agents such as
not raised appropriately. p-aminobenzoic acid and sulfinpyrazone will
Antimalarials decrease the methotrexate transport function of
renal tubules, thereby reducing excretion and
Pyrimethamine – increased anti-folate effect of almost certainly increasing methotrexate
methotrexate. toxicity.
Cardiac glycosides The use of nitrous oxide potentiates the effect of
methotrexate on folate metabolism, yielding
Digoxin absorption decreased by cytotoxics.
increased toxicity such as severe, unpredictable
Ciclosporin myelosuppression, stomatitis and neurotoxicity
with intrathecal administration. Whilst this
Increased risk of toxicity. effect can be reduced by administering calcium
Corticosteroids folinate, the concomitant use should be avoided.

Increased risk of haematological toxicity. 4.6 Fertility, Pregnancy and lactation

Cytotoxics Women of childbearing potential/Contraception
in females
Increased risk of pulmonary toxicity (see
sections 4.4 & 4.8). Women must not get pregnant during
methotrexate therapy, and effective
Immunosuppressants contraception must be used during treatment
Leflunomide – risk of toxicity (see also section with methotrexate and at least 6 months
4.4). thereafter (see section 4.4). Prior to initiating
therapy, women of childbearing potential must
Theophylline be informed of the risk of malformations
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associated with methotrexate and any existing Methotrexate is a powerful human teratogen,
pregnancy must be excluded with certainty by with an increased risk of spontaneous abortions,
taking appropriate measures, e.g. a pregnancy intrauterine growth restriction and congenital
test. During treatment pregnancy tests should be malformations in case of exposure during
repeated as clinically required (e.g. after any gap pregnancy.
of contraception). Female patients of
reproductive potential must be counselled • Spontaneous abortions have been reported in
regarding pregnancy prevention and planning. 42.5% of pregnant women exposed to low-dose
methotrexate treatment (less than 30 mg/week),
Contraception in males compared to a reported rate of 22.5% in disease-
matched patients treated with drugs other than
It is not known if methotrexate is present in methotrexate.
semen. Methotrexate has been shown to be
genotoxic in animal studies, such that the risk of • Major birth defects occurred in 6.6% of live
genotoxic effects on sperm cells cannot births in women exposed to low-dose
completely be excluded. Limited clinical methotrexate treatment (less than 30 mg/week)
evidence does not indicate an increased risk of during pregnancy, compared to approximately
malformations or miscarriage following paternal 4% of live births in disease-matched patients
exposure to low-dose methotrexate (less than 30 treated with drugs other than methotrexate.
mg/week). For higher doses, there is insufficient
data to estimate the risks of malformations or Insufficient data is available for methotrexate
miscarriage following paternal exposure. exposure during pregnancy higher than 30
mg/week, but higher rates of spontaneous
As precautionary measures, sexually active male abortions and congenital malformations are
patients or their female partners are expected, in particular at doses commonly used
recommended to use reliable contraception in oncologic indications.
during treatment of the male patient and for at
least 6 months after cessation of methotrexate. When methotrexate was discontinued prior to
Men should not donate semen during therapy or conception, normal pregnancies have been
for 6 months following discontinuation of reported.
methotrexate. When used in oncological indications,
Pregnancy methotrexate should not be administered during
pregnancy in particular during the first trimester
Methotrexate is contraindicated during of pregnancy. In each individual case the benefit
pregnancy in non-oncological indications (see of treatment must be weighed up against the
section 4.3). If pregnancy occurs during possible risk to the foetus. If the drug is used
treatment with methotrexate and up to six during pregnancy or if the patient becomes
months thereafter, medical advice should be pregnant while taking methotrexate, the patient
given regarding the risk of harmful effects on should be informed of the potential risk to the
the child associated with treatment and foetus.
ultrasonography examinations should be
Breast-feeding
performed to confirm normal foetal
development. As methotrexate passes into breast milk and may
In animal studies, methotrexate has shown cause toxicity in nursing infants, treatment is
contraindicated during the lactation period (see
reproductive toxicity, especially during the first
trimester (see section 5.3). Methotrexate has section 4.3). Breast-feeding is therefore to be
stopped prior to treatment.
been shown to be teratogenic to humans; it has
been reported to cause foetal death, miscarriages Fertility
and/or congenital abnormalities (e.g.
craniofacial, cardiovascular, central nervous Methotrexate affects spermatogenesis and
system and extremity-related). oogenesis and may decrease fertility. In humans,
methotrexate has been reported to cause
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oligospermia, menstrual dysfunction and 1/1000 to < 1/100); rare (≥ 1/10,000 to <
amenorrhoea. These effects appear to be 1/1,000); very rare (< 1/10,000), not known
reversible after discontinuation of therapy in (cannot be estimated from the available data).
most cases. In oncologic indications, women
Common Uncommon Rare Very rare Not
who are planning to become pregnant are known
advised to consult a genetic counselling centre, Infections Infections Opportunisti Herpes Sepsis
and c infections zoster resulting
if possible, prior to therapy and men should seek infestation Sepsis in death
advice about the possibility of sperm s Neutropenic
sepsis
preservation before starting therapy as leading to
methotrexate can be genotoxic at higher doses fatality

(see section 4.4). Neoplasm Lymphoma1

s benign,
malignant
4.7 Effects on ability to drive and use and
unspecifie
machines d
Methotrexate can cause dizziness, fatigue, (including
cysts and
blurred vision and eye-irritation, which may polyps)
affect the ability to drive or operate machinery. Blood and Leucopenia Bone Hypogam Pancytop
lymphatic marrow maglobuli enia,
system depression naemia, eosinophil
4.8 Undesirable Effects disorders manifested Lymphopr ia
by oliferative
leucopenia disorders
Generally the frequency and severity of adverse and
reactions are dependent of the size of the dose, thrombocyt
openia
the dosing frequency, the method of (which are
usually
administration and the duration of exposure. reversible)
Anaemia
If adverse reactions occur, the dose should be Immune Anaphylacti
reduced or therapy discontinued and necessary system c type
disorders reaction
corrective therapeutic measures undertaken,
Endocrine Diabetes
such as administration of calcium folinate (see disorders mellitus
sections 4.2 and 4.4). Psychiatric Depression Mood
disorders Confusion alteration
The most common adverse reactions of Transient
subtle
methotrexate are bone marrow suppression and cognitive
dysfunctio
mucosal damage which manifest as ulcerative n
stomatitis, leucopenia, nausea and other Nervous Headache Hemiparesis Irritation Drowsines
gastrointestinal disorders. These adverse system Dizziness (following Dysarthria s
disorders Fatigue administratio Aphasia Ataxia
reactions are generally reversible and corrected n of higher (following Paresis &
in about two weeks after the single dose of doses) administra Convulsio
tion of ns
methotrexate has been reduced or dose interval higher (following
increased and/or calcium folinate is used. Other doses) administra
Lethargy tion of
frequently occurring adverse reactions include higher
doses)
e.g. malaise, abnormal fatigue, chills and fever, Unusual
dizziness and reduced immunity to infections. cranial
sensation
s
Methotrexate causes adverse reactions most at
Eye Conjunctiv
high and frequently repeated doses, e.g. in the disorders itis
treatment of cancer diseases. Adverse reactions Blurred
vision
reported on methotrexate are given below Cardiac Pericardia Myocardia
according to organ systems. disorders l effusion l ischemia
Pericarditi
The frequencies of the adverse reactions are s

classified as follows: Very common (≥ 1/10); Vascular

disorders
Nosebleed Hypotension Vasculitis
Thromboemb
common (≥ 1/100 to < 1/10); uncommon (≥ olism
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Respirator Pneumoniti Dyspnoea Pneumoc Acute Renal and Renal Dysuria Renal
y, thoracic s Pharyngitis2 ystis pulmonary urinary insufficienc Azotaemi failure and
and acute or Pulmonary carinii – oedema disorders y a uraemia
mediastina chronic fibrosis pneumoni (after oral Nephropath Cystitis may
l disorders interstitial a and y Haematuri follow
pneumonitis Chronic intrathecal a methotrex
often interstitial use) ate
associated obstructiv Syndrome administra
with blood e lung consisting tion,
eosinophilia disease of pleuritic particularl
(can be Pleuritis pain and y after
fatal) Dry cough pleural high
Interstitial thickening doses or
fibrosis has been prolonged
reported administra
following tion
high
Pregnancy Miscarriag
doses,
, e, fetal
alveolitis,
puerperiu damages
Pulmonar
m and
y alveolar
perinatal
haemorrh
3 conditions
age
Reproducti Vaginal Decreased Formation Vaginitis
Gastrointe Stomatitis Gingivitis Haemate Mucositis
ve system ulceration libido of
stinal Anorexia Gastrointesti mesis
and breast Impotence defective
disorders4 Nausea nal
disorders Menstrual oocytes or
Vomiting ulcerations
disorders sperm
Diarrhoea and
cells
haemorrhage
Transient
Enteritis
oligosper
The effect of
mia,
Methotrexate
Infertility-
on the
this effect
intestinal
appears
mucosa has
to be
led to
reversible
malabsorptio
after
n or toxic
discontinu
megacolon
ation of
Hepatobili Elevated Hepatotoxicit therapy
ary transamina y resulting in (see
disorders se acute liver section
concentrati atrophy, 4.6)
ons necrosis, Vaginal
fatty bleeding
metamorpho Gynaeco
sis, periportal mastia
fibrosis, liver
Injury, Increased
cirrhosis or
poisoning risk of
death usually
and toxic
following
procedural reactions
chronic
complicati (soft
administratio
ons tissue
n
necrosis,
Acute
osteonecr
hepatitis
osis)
Skin and Erythemato Pruritus Photohypers Telangiect during
subcutane us rash Stevens- ensitivity asis radiothera
ous tissue Alopecia Johnson´s Acne Furunculo py
disorders syndrome Depigmentati sis
Toxic on Ecchymos
epidermal Urticaria es
necrolysis Erythema 1
multiforme
Can be reversible (see section 4.4).
Painful 2
damage to See section 4.4.
psoriatic
3
lesion (has been reported for methotrexate used in
Skin
ulceration rheumatologic and related indications)
Musculosk Osteoporosis Osteonecr 4
eletal and Arthralgia osis of jaw Gastrointestinal severe adverse reactions
connective Myalgia (secondar require often dose reduction. Ulcerative
tissue Increased y to
disorders rheumatic lymphopro stomatitis and diarrhoea require discontinuation
nodules liferative
disorders)
of methotrexate therapy because of the risk of
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ulcerative enteritis and fatal intestinal Cases of overdose have been reported,
perforation. sometimes fatal, due to erroneous daily intake
instead of weekly intake of oral methotrexate. In
The psoriatic lesions may get worse from these cases, symptoms that have been commonly
simultaneous exposure to methotrexate and reported are haematological and gastrointestinal
ultraviolet radiation. reactions.
In the treatment of rheumatoid arthritis, The toxicity of methotrexate affects mainly the
methotrexate induced lung disease is a haematopoietic organs. Calcium folinate
potentially serious adverse drug reaction which
neutralises effectively the immediate
may occur acutely at any time during therapy. It
haematopoietic toxic effects of methotrexate.
is not always fully reversible. Pulmonary Parenteral calcium folinate therapy should be
symptoms (especially a dry, non productive started within one hour after the administration
cough) may require interruption of treatment and of methotrexate. The dose of calcium folinate
careful investigation.
should be at least as high as the dose of
There have been reports of leucoencephalopathy methotrexate received by the patient.
following intravenous methotrexate in high
Massive overdose requires hydration and
doses, or low doses following cranial-spinal alkalinisation of the urine to prevent
radiation.
precipitation of methotrexate and/or its
Other reports include eye irritation, abnormal metabolites in the renal tubules. Haemodialysis
(usually "megaloblastic") red cell morphology, or peritoneal dialysis has not been found to
precipitation of diabetes, other metabolic affect the elimination of methotrexate. Instead,
changes, and sudden death in relation to or effective clearance of methotrexate has been
attributed to the use of methotrexate. achieved by intermittent haemodialysis using a
so-called “high-flux” dialyser.
In rare cases, following intrathecal
administration, a tumour lysis syndrome has Observation of serum methotrexate
been observed. Features include hyperkalaemia, concentrations is relevant in determining the
hyperuricaemia and hyperphosphataemia with right dose of calcium folinate and the duration of
hypocalcaemia; renal damage and arrhythmias the therapy.
can follow.
5. PHARMACOLOGICAL
Reporting of suspected adverse reactions PROPERTIES
Reporting suspected adverse reactions after 5.1 Pharmacodynamic properties
authorisation of the medicinal product is
important. It allows continued monitoring of the Pharmacotherapeutic group: Other
benefit/risk balance of the medicinal product. immunosuppressive agents, Mechanism of
4.9 Overdose action

Symptoms and Management Methotrexate (4-amino-10-methylfolic acid) is a

folic acid antagonist which inhibits the reduction
Leucovorin is a specific antidote for of folic acid and increase of tissue cells. Its main
methotrexate and, following accidental effect is inhibition of DNA synthesis but it also
overdosage, should be administered within one acts directly both on RNA and protein synthesis.
hour at a dosage equal to, or greater than, the
methotrexate dose. It may be administered by Methotrexate enters the cell through an active
i.v. bolus or infusion. Further doses may be transport mechanism of reduced folates. As a
required. The patient should be observed result of polyglutamation of methotrexate caused
carefully and blood transfusions, renal dialysis by the folylpolyglutamylate enzyme, the
and reverse barrier nursing may be necessary. duration of the cytotoxic effect of the drug
substance in the cell increases. Methotrexate is a
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phase-specific substance the main action of Elimination:

which is directed to the S-phase of cell mitosis.
It acts generally most effectively on actively The elimination follows a triphasic pattern.
increasing tissues, such as malignant cells, bone Excretion takes place mainly via the kidneys.
marrow, fetal cells, skin epithelium, oral and Approximately 41% of the dose is excreted
intestinal mucosa as well as urinary bladder unchanged in the urine within the first six hours,
cells. As the proliferation of malignant cells is 90% within 24 hours. A minor part of the dose is
excreted in the bile of which there is pronounced
higher than that of most normal cells,
enterohepatic circulation.
methotrexate can slow down the proliferation of
malignant cells without causing, irreversible The half-life is approximately 3–10 hours
damage to normal tissue. following low dose treatment and 8–15 hours
Calcium folinate is a folinic acid which is used following high dose treatment. If the renal
to protect normal cells from the toxic effects of function is impaired, the concentration of
methotrexate in serum and in tissues may
methotrexate. Calcium folinate enters the cell
increase rapidly.
through a specific transport mechanism, is
converted in the cell into active folates and 5.3 Preclinical safety data
reverses the inhibition of the precursor synthesis
caused by the DNA and RNA. Chronic toxicity studies in mice, rats and dogs
showed toxic effects in the form of
Methotrexate is a folic acid antagonist and its gastrointestinal lesions, myelosuppression and
major site of action is the enzyme dihydrofolate hepatotoxicity. Animal studies show that
reductase. The inhibition of dihydrofolate methotrexate impairs fertility, and is embryo-
reductase can be circumvented by the use of and foetotoxic. Teratogenic effects have been
leucovorin (folinic acid; citrovorum factor) and identified in four species (rats, mice, rabbits,
protection of normal tissues can be carried out cats). In rhesus monkeys no malformations
by properly timed administration of leucovorin occurred. Methotrexate is mutagenic in vivo and
calcium. in vitro. There is evidence that methotrexate
5.2 Pharmacokinetic properties causes chromosomal aberrations in animal cells
and in human bone marrow cells, but the clinical
Absorption: significance of these findings has not been
established. Rodent carcinogenicity studies do
The effect of orally administered methotrexate not indicate an increased incidence of tumours.
seems to be dependent on the size of the dose.
When given in low doses, methotrexate is 6. PHARMACEUTICAL
rapidly absorbed from the GI tract giving plasma PARTICULARS
concentrations equivalent to those achieved after
i.v. administration. Peak concentrations in serum 6.1 List of excipients
are reached within 1–2 hours. Generally a dose Lactose monohydrate, Magnesium Stearate,
of methotrexate of 30 mg/m2 or less is absorbed Starch Pregelatinised and Sodium Hydroxide.
rapidly and completely. The bioavailability of
orally administered methotrexate is high (80– 6.2 Incompatibilities
100%) at doses of 30 mg/m2or less. Saturation of
Not applicable.
the absorption starts at doses above 30 mg/m2
and absorption at doses exceeding 80 mg/m2 is 6.3 Shelf life
incomplete.
Distribution: 3 years.

About half of the absorbed methotrexate binds 6.4 Special precautions for storage
reversibly to serum protein, but is readily
distributed in tissues. Do not store above 25°C.
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Store in original container in order to protect from

light.

6.5 Nature and contents of container

Polypropylene bottles -28 or 100 tablets
HDPE bottles- 28 or 100 tablets
PVC/Aluminium blisters – 24, 28 or 30 tablets
Not all pack sizes may be marketed
6.6 Special precautions for disposal and
other handling
Cytotoxic drugs should only be handled by
trained personnel in a designated area. The work
surface should be covered with disposable
plastic-backed absorbent paper.
Protective gloves and goggles should be worn to
avoid the drug accidentally coming into contact
with the skin or eyes.
Methotrexate is not vesicant and should not
cause harm if it comes in contact with the skin.
It should, of course, be washed off with water
immediately. Any transient stinging may be
treated with bland cream. If there is any danger
of systemic absorption of significant quantities
of methotrexate, by any route, Calcium
Leucovorin cover should be given.
Cytotoxic preparations should not be handled by
pregnant staff.
Any spillage or waste material may be disposed
of by incineration. We do not make any specific
recommendations with regards to the
temperature of the incinerator.
Any unused medicinal product or waste material
should be disposed of in accordance with local
requirements.
7. MANUFACTURER:

Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)