METHOTREXATE TABLET 2.5MG

Active substance: METHOTREXATE

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PRODUCT SUMMARY
1.

NAME OF THE MEDICINAL PRODUCT

Methotrexate 2.5 mg Tablets.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Methotrexate 2.5 mg per tablet.
For excipients see 6.1.

3.

PHARMACEUTICAL FORM
Tablet for oral administration.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Methotrexate is indicated in the treatment of neoplastic disease, such as
trophoblastic neoplasms and leukaemia and in the control of severe
recalcitrant psoriasis which is not responsive to other forms of therapy.
Methotrexate is used in the treatment of adults with severe, active, classical or
definite rheumatoid arthritis who are unresponsive or intolerant to
conventional therapy.

4.2.

Posology and method of administration
Adults and children
Antineoplastic Chemotherapy
Methotrexate is active orally and parenterally. Methotrexate Injection B.P. may be
given by the intramuscular, intravenous, intra-arterial or intrathecal routes. Dosage is
related to the patient's body weight or surface area. Methotrexate has been used with
beneficial effect in a wide variety of neoplastic diseases, alone and in combination
with other cytotoxic agents.
Choriocarcinoma and Similar Trophoblastic Diseases

Methotrexate is administered orally or intramuscularly in doses of 15-30 mg daily for
a 5-day course. Such courses may be repeated 3-5 times as required, with rest periods
of one or more weeks interposed between courses until any manifesting toxic
symptoms subside.
The effectiveness of therapy can be evaluated by 24 hour quantitative analysis of
urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other
cytotoxic drugs, has also been reported as useful.
Hydatidiform mole may precede or be followed by choriocarcinoma, and
methotrexate has been used in similar doses for the treatment of hydatidiform mole
and chorioadenoma destruens.
Breast Carcinoma
Prolonged cyclic combination with Cyclophosphamide, methotrexate and
Fluorouracil has given good results when used as adjuvant treatment to radical
mastectomy in primary breast cancer with positive axillary lymph nodes.
Methotrexate dosage was 40 mg/m2 intravenously on the first and eighth days.
Leukaemia
Acute granulocytic leukaemia is rare in children but common in adults and this form
of leukaemia responds poorly to chemotherapy.
Methotrexate is not generally a drug of choice for induction of remission of
lymphoblastic leukaemia. Oral methotrexate 3.3 mg/m2 daily, and Prednisolone 4060 mg/m2 daily for 4-6 weeks has been used. After a remission is attained,
methotrexate in a maintenance dosage of 20-30 mg/m2 orally or by I.M. injection has
been administered twice weekly. Twice weekly doses appear to be more effective
than daily drug administration. Alternatively, 2.5 mg/kg has been administered I.V.
every 14 days.
Meningeal Leukaemia
Some patients with leukaemia are subject to leukaemic invasions of the central
nervous system and the CSF should be examined in all leukaemia patients.
Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for
adequate therapy the drug should be administered intrathecally. Methotrexate may be
given in a prophylactic regimen in all cases of lymphocytic leukaemia. Methotrexate
is administered by intrathecal injection in doses of 200-500 microgram/kg body
weight. The administration is at intervals of 2 to 5 days and is usually repeated until
the cell count of cerebrospinal fluid returns to normal. At this point one additional
dose is advised. Alternatively, methotrexate 12 mg/m2 can be given once weekly for
2 weeks, and then once monthly. Large doses may cause convulsions and untoward
side effects may occur as with any intrathecal injection, and are commonly
neurological in character.
Lymphomas
In Burkitt's Tumour, stages 1-2, methotrexate has prolonged remissions in some
cases. Recommended dosage is 10-25 mg per day orally for 4 to 8 days. In stage 3,
methotrexate is commonly given concomitantly with other antitumour agents.
Treatment in all stages usually consists of several courses of the drug interposed with
7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with
methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily. Hodgkin's Disease
responds poorly to methotrexate and to most types of chemotherapy.

Mycosis Fungoides
Therapy with methotrexate appears to produce clinical remissions in one half of the
cases treated. Recommended dosage is usually 2.5 to 10 mg daily by mouth for
weeks or months and dosage should be adjusted according to the patient's response
and haematological monitoring. Methotrexate has also been given intramuscularly in
doses of 50 mg once weekly or 25 mg twice weekly.
Psoriasis Chemotherapy
This medicine should be taken once a week.
The prescriber may specify the day of intake on the prescription.
Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have
responded to weekly single, oral, I.M. or I.V. doses of 10-25 mg per week, adjusted
according to the patient's response. An initial test dose one week prior to initiation of
therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10
mg.
An alternative dosage schedule consists of 2.5 to 5 mg of methotrexate administered
orally at 12 hour intervals for 3 doses each week or at 8-hour intervals for 4 doses
each week; weekly dosages should not exceed 30 mg.
A daily oral dosage schedule of 2 to 5 mg administered orally for 5 days followed by
a rest period of at least 2 days may also be used. The daily dose should not exceed
6.25 mg.
The patient should be fully informed of the risks involved and the clinician should
pay particular attention to the appearance of liver toxicity by carrying out liver
function tests before starting methotrexate treatment, and repeating these at 2 to 4
month intervals during therapy. The aim of therapy should be to reduce the dose to
the lowest possible level with the longest possible rest period. The use of
methotrexate may permit the return to conventional topical therapy which should be
encouraged.
Rheumatoid arthritis
This medicine should be taken once a week.
The prescriber may specify the day of intake on the prescription.
Careful monitoring should be undertaken after the first dose of methotrexate to
exclude idiosyncratic hypersensitivity reactions.
Adults:
In adults with severe, active, classical or definite rheumatoid arthritis who are
unresponsive or intolerant to conventional therapy, 7.5 mg orally once weekly or
divided oral doses of 2.5 mg at 12 hour intervals for 3 doses (7.5 mg) as a course once
weekly. The schedule may be adjusted gradually to achieve an optimal response but
should not exceed a total weekly dose of 20 mg. Once response has been achieved,
the schedule should be reduced to the lowest possible effective dose.
Elderly:
Methotrexate should be used with extreme caution in elderly patients, a reduction in
dosage should be considered.
Children:
Safety and effectiveness in children have not been established, other than in cancer
chemotherapy.

4.3.

Contraindications
Liver disease including fibrosis, cirrhosis, recent or active hepatitis;
Active infections;
Overt or laboratory evidence of immunodeficiency syndrome(s);
Significantly impaired renal function.
Significantly impaired hepatic function
Pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia,
thrombocytopenia or anaemia.
Methotrexate is contraindicated in pregnancy.
Due to the potential for serious adverse reactions from methotrexate in breast fed
infants, breast feeding is contra-indicated in women taking methotrexate.
Patients with a known allergic hypersensitivity to methotrexate should not receive
methotrexate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

4.4.

Special warnings and precautions for use
Warnings
Methotrexate must be used only by physicians experienced in antimetabolite
chemotherapy.
Concomittant administration of hepatotoxic or haematotoxic DMARDs (e.g.
leflunomide) is not advisable.
Due to the possibility of fatal or severe toxic reactions, the patient should be fully
informed by the physician of the risks involved and be under his constant supervision.
The carton and bottle label will state: “Check dose and frequency – methotrexate is
usually taken once a week.”
Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia,
may occur and deaths have been reported. Symptoms typically include dyspnoea,
cough (especially a dry non-productive cough) and fever for which patients should be
monitored at each follow-up visit. Patients should be informed of the risk of
pneumonitis and advised to contact their doctor immediately should they develop
persistent cough or dyspnoea.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a
thorough investigation should be made to exclude infection. If methotrexate induced
lung disease is suspected treatment with corticosteroids should be initiated and
treatment with methotrexate should not be restarted.
When a patient presents with pulmonary symptoms, the possibility of Pneumocystis
carinii pneumonia should be considered.
Methotrexate has the potential for serious, sometimes fatal toxicity. The toxic effects
may be related in frequency and severity to the dose or frequency of administration
but have been seen at all doses. Because the toxic reactions can occur at any time
during therapy, the patients have to be observed closely and must be informed of
early signs and symptoms of toxicity.
Use caution when administering high-dose methotrexate to patients receiving proton
pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic
studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole
and pantoprazole, with methotrexate (primarily at high dose), may elevate and
prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate,
possibly leading to methotrexate toxicities. In two of these cases, delayed
methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs, but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of
methotrexate with ranitidine have been conducted.
The carton and bottle label will state: “Check dose and frequency – methotrexate is
usually taken once a week.”
Deaths have been reported with the use of methotrexate in the treatment of psoriasis.
In the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant,
disabling psoriasis which is not adequately responsive to other forms of therapy, but
only when the diagnosis has been established by biopsy and/or after dermatological
consultation.
The prescriber may specify the day of intake on the prescription.
Patients should be aware of importance of adhering to the once weekly intakes.
1. Full blood counts should be closely monitored before, during and after treatment.
If a clinically significant drop in white-cell or platelet count develops,
methotrexate should be withdrawn immediately. Patients should be advised to
report all symptoms or signs suggestive of infection.
2. Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged
therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis
have been reported. Since changes may occur without previous signs of
gastrointestinal or haematological toxicity, it is imperative that hepatic function
be determined prior to initiation of treatment and monitored regularly throughout
therapy. If substantial hepatic function abnormalities develop, methotrexate
dosing should be suspended for at least 2 weeks. Special caution is indicated in
the presence of pre-existing liver damage or impaired hepatic function.
Concomitant use of other drugs with hepatotoxic potential (including alcohol)
should be avoided.

3. Methotrexate has been shown to be teratogenic; it has caused foetal death and/or
congenital anomalies. Therefore it is not recommended in women of
childbearing potential unless there is appropriate medical evidence that the
benefits can be expected to outweigh the considered risks. Pregnant psoriatic
patients should not receive methotrexate.
4. Renal function should be closely monitored before, during and after treatment.
Caution should be exercised if significant renal impairment is disclosed. Reduce
dose of methotrexate in patients with renal impairment. High doses may cause
the precipitation of methotrexate or its metabolites in the renal tubules. A high
fluid throughput and alkalinisation of the urine to pH 6.5 – 7.0, by oral or
intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three
hours) or acetazolamide (500 mg orally four times a day) is recommended as a
preventative measure. Methotrexate is excreted primarily by the kidneys. Its use
in the presence of impaired renal function may result in accumulation of toxic
amounts or even additional renal damage.
5. Diarrhoea and ulcerative stomatitis are frequent toxic effects and require
interruption of therapy, otherwise haemorrhagic enteritis and death from
intestinal perforation may occur.
6. Methotrexate affects gametogenesis during the period of its administration and
may result in decreased fertility which is thought to be reversible on
discontinuation of therapy. Conception should be avoided during the period of
methotrexate administration and for at least 6 months thereafter. Patients and
their partners should be advised to this effect.
7. Methotrexate has some immunosuppressive activity and immunological
responses to concurrent vaccination may be decreased. The immunosuppressive
effect of methotrexate should be taken into account when immune responses of
patients are important or essential. Immunization with live virus vaccines is
generally not recommended.
8. Pleural effusions and ascites should be drained prior to initiation of methotrexate
therapy.
9. Deaths have been reported with the use of methotrexate. Serious adverse
reactions including deaths have been reported with concomitant administration of
methotrexate (usually in high doses) along with some non-steroidal antiinflammatory drugs (NSAIDs).
10. Concomitant administration of folate antagonists such as
trimethoprim/sulphamethoxazole has been reported to cause an acute
megaloblastic pancytopenia in rare instances.
11. Systemic toxicity may occur following intrathecal administration. Blood counts
should be monitored closely.
12. A chest X-ray is recommended prior to initiation of methotrexate therapy.
13. If acute methotrexate toxicity occurs, patients may require folinic acid.
14. Severe, occasionally fatal, cutaneous or sensitivity reactions (e.g., toxic epidermic
necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis,
erythema multiforme, vasculitis and extensive herpetiform skin eruptions) may

occur after the administration of methotrexate and recovery ensured mostly after
discontinuation of the therapy.
Precautions
Methotrexate has a high potential toxicity, usually dose related, and should be used
only by physicians experienced in antimetabolite chemotherapy, in patients under
their constant supervision. The physician should be familiar with the various
characteristics of the drug and its established clinical usage.
Before beginning methotrexate therapy or reinstituting methotrexate after a rest
period, assessment of renal function, liver function and blood elements should be
made by history, physical examination and laboratory tests.
It should be noted that intrathecal doses are transported into the cardiovascular system
and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be
enhanced in patients with renal dysfunction, ascites, or other effusions due to
prolongation of serum half-life.
Malignant Lymphomas may occur in patients receiving low dose methotrexate, in
which case therapy must be discontinued. Failure of the Lymphoma to show signs of
spontaneous regression requires the initiation of cytotoxic therapy.
Carcinogenesis, mutagenesis, and impairment of fertility: Animal carcinogenicity
studies have demonstrated methotrexate to be free of carcinogenic potential.
Although methotrexate has been reported to cause chromosomal damage to animal
somatic cells and bone marrow cells in humans, these effects are transient and
reversible. In patients treated with methotrexate, evidence is insufficient to permit
conclusive evaluation of any increased risk of neoplasia.
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 patients of childbearing potential (see 'Warnings').
Patients undergoing therapy should be subject to appropriate supervision so that signs
or symptoms of possible toxic effects or adverse reactions may be detected and
evaluated with minimal delay. Pretreatment and periodic haematological studies are
essential to the use of methotrexate in chemotherapy because of its common effect of
haematopoietic suppression. This may occur abruptly and on apparent safe dosage,
and any profound drop in blood cell count indicates immediate stopping of the drug
and appropriate therapy. In patients with malignant disease who have pre-existing
bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should
be used with caution, if at all.
In general, the following laboratory tests are recommended as part of essential clinical
evaluation and appropriate monitoring of patients chosen for or receiving
methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function
tests; liver function tests and chest X-ray.
The purpose is to determine any existing organ dysfunction or system impairment.
The tests should be performed prior to therapy, at appropriate periods during therapy
and after termination of therapy.

Liver biopsy may be considered after cumulative doses > 1.5g have been given, if
hepatic impairment is suspected.
Methotrexate is bound in part to serum albumin after absorption, and toxicity may be
increased because of displacement by certain drugs such as salicylates,
sulphonamides, phenytoin, and some antibacterials such as tetracycline,
chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and
sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given
concurrently until the significance of these findings is established.
Vitamin preparations containing folic acid or its derivatives may alter response to
methotrexate.
Methotrexate should be used with extreme caution in the presence of infection, peptic
ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound
leukopenia occurs during therapy, bacterial infection may occur or become a threat.
Cessation of the drug and appropriate antibiotic therapy is usually indicated. In
severe bone marrow depression, blood or platelet transfusions may be necessary.
Since it is reported that methotrexate may have an immunosuppressive action, this
factor must be taken into consideration in evaluating the use of the drug where
immune responses in a patient may be important or essential.
In all instances where the use of methotrexate is considered for chemotherapy, the
physician must evaluate the need and usefulness of the drug against the risks of toxic
effects or adverse reactions. Most such adverse reactions are reversible if detected
early. When such effects or reactions do occur, the drug should be reduced in dosage
or discontinued and appropriate corrective measures should be taken according to the
clinical judgement of the physician. Reinstitution of methotrexate therapy should be
carried out with caution, with adequate consideration of further need for the drug and
alertness as to the possible recurrence of toxicity.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft
tissue necrosis and osteonecrosis.

4.5.

Interaction with other medicinal products and other forms of interaction
Methotrexate is extensively protein bound and may be displaced by certain drugs
such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins,
tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic antiinflammatory agents, so causing a potential for increased toxicity when used
concurrently.
Concomitant use of other drugs with nephrotoxic,myelotoxic or hepatotoxic potential
such as leflunomide, azathioprine, sulphasalazine, retinoids and alcohol should be
avoided.
Vitamin preparations containing folic acid or its derivatives may decrease the
effectiveness of methotrexate.
Caution should be used when NSAIDs and salicylates are administered concomitantly
with methotrexate. These drugs have been reported to reduce the tubular secretion of

methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and
salicylates has been associated with fatal methotrexate toxicity.
However, patients using constant dosage regimens of NSAIDs have received
concurrent doses of methotrexate without problems observed.
Renal tubular transport is also diminished by probenecid and penicillins; use of these
with methotrexate should be carefully monitored.
A potential interaction may exist between methotrexate and proton-pump inhibitors
(e.g. omeprazole, pantoprazole). Omeprazole may inhibit methotrexate clearance
resulting in potentially toxic methotrexate levels.
Severe bone marrow depression has been reported following the concurrent use of
methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be
avoided.
Methotrexate-induced stomatitis and other toxic effects may be increased by the use
of nitrous oxide.
An increased risk of hepatitis has been reported following the use of methotrexate and
the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate
and acitretin should be avoided.
Methotrexate may increase the bioavailability of mercaptopurine by interference with
first-pass metabolism.
Concomitant application of methotrexate and theophylline can reduce theophylline
clearance.

4.6.

Pregnancy and lactation
Abortion, foetal death, and/or congenital anomalies have occurred in pregnant
women receiving methotrexate, especially during the first trimester of
pregnancy. Methotrexate is contraindicated in the management of psoriasis or
rheumatoid arthritis in pregnant women. Women of childbearing potential
should not receive methotrexate until pregnancy is excluded. For the
management of psoriasis or rheumatoid arthritis, methotrexate therapy in
women should be started immediately following a menstrual period and
appropriate measures should be taken in men or women to avoid conception
during and for at least 6 months following cessation of methotrexate therapy.
Both men and women receiving methotrexate should be informed of the
potential risk of adverse effects on reproduction. Women of childbearing
potential should be fully informed of the potential hazard to the foetus should
they become pregnant during methotrexate therapy. In cancer chemotherapy,
methotrexate should not be used in pregnant women or women of childbearing
potential who might become pregnant unless the potential benefits to the
mother outweigh the possible risks to the foetus.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual
dysfunction, and infertility have been reported in patients receiving
methotrexate.
Methotrexate is distributed into breast milk. Because of the potential for
serious adverse reactions to methotrexate in nursing infants, a decision should
be made whether to discontinue nursing or the drug, taking into account the
importance of the drug to the woman.

4.7.

Effects on ability to drive and use machines
Not applicable.

4.8.

Undesirable effects
The most common adverse reactions include ulcerative stomatitis, leukopenia,
vasculitis, eye-irritation and loss of libido/impotence, nausea and abdominal distress.
Although very rare, anaphylactic reactions to methotrexate have occurred. Others
reported are malaise, undue fatigue, chills and fever, dizziness and decreased
resistance to infection. In general, the incidence and severity of side effects are
considered to be dose-related. Adverse reactions as reported for the various systems
are as follows:
Skin: Severe, occasionally fatal, dermatologic reactions including erythema
multiforme, Stevens-Johnson syndrome, skin necrosis, exfoliative dermatitis,
epidermal necrolysis. Erythematous rashes, pruritus, urticaria, dermatitis,
photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne,
furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to
ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of
psoriatic plaques have been reported. The recall phenomenon has been reported in
both radiation and solar damaged skin.
Blood: Bone marrow depression, leukopenia, thrombocytopenia, anaemia,
hypogammaglobulinaemia, haemorrhage from various sites, septicaemia.
Alimentary System: Gingivitis, pharyngitis, stomatitis, mucositis, anorexia, vomiting,
diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding,
pancreatitis, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty
metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of
methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.
Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute
liver atrophy, necrosis, fatty metamorphosis, hepatitis, periportal fibrosis or cirrhosis
or death may occur, usually following chronic administration.
Urogenital System: Renal failure, azotaemia, cystitis, haematuria, defective
oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction,

infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers,
cystitis, haematuria and nephropathy have also been reported.
Pulmonary System: Acute or chronic interstitial pneumonitis, often associated with
blood eosinophilia, may occur and deaths have been reported (see Section 4.4 Special
warnings and special precautions for use). Acute pulmonary oedema has also been
reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome
consisting of pleuritic pain and pleural thickening has been reported following high
doses.
Central Nervous System: Headaches, drowsiness, blurred vision, aphasia, cognitive
disorder, hemiparesis and convulsions have occurred possibly related to haemorrhage
or to complications from intra-arterial catheterization. Convulsion, paresis, GuillainBarre syndrome and increased cerebrospinal fluid pressure have followed intrathecal
administration.
Other reactions related to, or attributed to the use of methotrexate such as
pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects,
abnormal changes in tissue cells and even sudden death have been reported.
There have been reports of leukoencephalopathy following intravenous methotrexate
in high doses, or low doses following cranial-spinal radiation.
Cardiac disorders: Pericarditis, pericardial effusion
Ear disorders: Tinnitus
Eye disorders: Conjunctivitis
Infections and infestations: Opportunistic infections (sometimes fatal e.g. fatal
sepsis) have also been reported in patients receiving methotrexate therapy for
neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the
most common. Other reported infections include, pneumonia, nocardiosis,
histoplasmosis, cryptococcosis, Herpes Zoster, Herpes Simplex, hepatitis and
cytomegalovirus infection, including cytomegaloviral pneumonia.
Musculoskeletal and connective tissue disorders: Arthralgia/myalgia
Psychiatric disorders: Mood altered
Vascular disorders: Hypotension, thromboembolic events (e.g. thrombophlebitis,
pulmonary embolism, arterial, cerebral, deep vein or retinal vein thrombosis).
Adverse reactions following intrathecal methotrexate are generally classified into
three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis
manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The
subacute form may include paresis, usually transient, paraplegia, nerve palsies, and
cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by
irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia,
somnolence, coma, and rarely, death. There is evidence that the combined use of
cranial radiation and intrathecal methotrexate increases the incidence of
leukoencephalopathy.

Additional reactions related to or attributed to the use of methotrexate such as
osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of
diabetes, other metabolic changes, and sudden death have been reported.
A small number of cases of accelerated nodulosis have been reported in the literature
it is unclear whether the development of accelerated nodulosis during methotrexate
therapy is a drug-related side effect or is part of the natural history of the rheumatoid
disease.

4.9.

Overdose
Cases of overdose, sometimes fatal, due to erroneous daily intake instead of weekly
intake of oral methotrexate have been reported. In these cases, symptoms that have
been commonly reported are haematological and gastrointestinal reactions.
Calcium folinate (Calcium Leucovorin) is a potent agent for neutralizing the
immediate toxic effects of methotrexate on the haematopoietic system. Where large
doses or overdoses are given, calcium folinate may be administered by intravenous
infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly
every 6 hours for 4 doses. Where average doses of methotrexate appear to have an
adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6
hours for 4 doses. In general, where overdosage is suspected, the dose of calcium
folinate should be equal to or higher than, the offending dose of methotrexate and
should be administered as soon as possible; preferably within the first hour and
certainly within 4 hours after which it may not be effective.
Other supporting therapy such as blood transfusion and renal dialysis may be
required. In cases of massive overdose, hydration and urinary alkalisation may be
necessary to prevent precipitation of methotrexate and/or its metabolites in the renal
tubules. Neither haemodialysis nor peritoneal dialysis has been shown to improve
methotrexate elimination. Effective clearance of methotrexate has been reported with
acute, intermittent haemodialysis using a high flux dialyser.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Methotrexate is an antimetabolite which acts principally by competitively
inhibiting the enzyme, dihydrofolate reductase. In the process of DNA
synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic
acid by this enzyme, and inhibition by methotrexate interferes with tissue cell
reproduction. Actively proliferating tissues such as malignant cells are
generally more sensitive to this effect of methotrexate. It also inhibits antibody
synthesis.
Methotrexate also has immunosuppressive activity, in part possibly as a result
of inhibition of lymphocyte multiplication. The mechanism(s) of action in the
management of rheumatoid arthritis of the drug is not known, although
suggested mechanisms have included immunosuppressive and/or antiinflammatory effect.

5.2.

Pharmacokinetic properties
In doses of 0.1 mg (of methotrexate) per kg, methotrexate is completely
absorbed from the G.I. tract; larger oral doses may be incompletely absorbed.
Peak serum concentrations are achieved within 0.5 - 2 hours following I.V. /
I.M. or intra-arterial administration. Serum concentrations following oral
administration of methotrexate may be slightly lower than those following I.V.
injection.
Methotrexate is actively transported across cell membranes. The drug is
widely distributed into body tissues with highest concentrations in the kidneys,
gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks
in the kidneys and for months in the liver. Sustained serum concentrations and
tissue accumulation may result from repeated daily doses. Methotrexate
crosses the placental barrier and is distributed into breast milk. Approximately
50% of the drug in the blood is bound to serum proteins.
In one study, methotrexate had a serum half-life of 2-4 hours following I.M.
administration. Following oral doses of 0.06 mg/kg or more, the drug had a
serum half-life of 2-4 hours, but the serum half-life was reported to be
increased to 8-10 hours when oral doses of 0.037 mg/kg were given.
Methotrexate does not appear to be appreciably metabolised. The drug is
excreted primarily by the kidneys via glomerular filtration and active
transport. Small amounts are excreted in the faeces, probably via the bile.
Methotrexate has a biphasic excretion pattern. If methotrexate excretion is
impaired accumulation will occur more rapidly in patients with impaired renal
function. In addition, simultaneous administration of other weak organic acids
such as salicylates may suppress methotrexate clearance.

5.3.

Pre-clinical safety data

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Other Constituents
Maize Starch
Lactose
Pre gelatinised Starch (Prejel PA5)

Polysorbate 80
Microcrystalline Cellulose (AVICEL 101)
Magnesium Stearate
There is no overage included in the formulation.

6.2.

Incompatibilities
Immediate precipitation or turbidity results when combined with certain
concentrations of Droperidol, Heparin Sodium, Metoclopramide
Hydrochloride, Ranitidine Hydrochloride in Syringe.

6.3.

Shelf life
60 months.

6.4.

Special precautions for storage
There are no specific storage requirements.

6.5.

Nature and content of container
White polyethylene bottle with high density polyethylene screw closure
containing 100 tablets.

6.6.

Instructions for use and handling, (and disposal)
Not applicable.

No Data Held

7

MARKETING AUTHORISATION HOLDER

Hospira UK Limited
Queensway

Royal Leamington Spa
Warwickshire
CV31 3RW
UK
8.
MARKETING AUTHORISATION NUMBER
PL: 04515/0004.

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24th April 2002.

10

DATE OF REVISION OF THE TEXT
21/01/2014

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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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