SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Methotrexate 10mg Tablets BP

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Methotrexate 10mg For excipients see 6.1

3    PHARMACEUTICAL FORM

Tablet

Methotrexate 10mg Tablets are light yellow, capsule shaped tablets with a score on one side, with a major axis of 15mm and a minor axis of 7mm; may contain yellow to red sprinkles.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of acute lymphoblastic leukaemia and Burkitt’s lymphoma. The treatment of severe cases of uncontrolled psoriasis, unresponsive to conventional therapy.

4.2    Posology and method of administration

For oral administration. Dosages are based on the patient's body weight or surface area. Doses should be reduced in cases of haematological deficiency and hepatic or renal impairment.

This medicine should be taken once a week.

The prescriber may specify the day of intake on the prescription.

Acute Lymphoblastic Leukaemia: Children

In acute lymphoblastic leukaemia remissions are usually best induced with a combination of corticosteroids and other cytotoxic agents.

Methotrexate 15mg/m², given orally once weekly, in combination with other drugs, appears to be the treatment of choice for maintenance of drug-induced remissions.

Burkitt’s Lymphoma: Children

Some cases of Burkitt's lymphoma, when treated in the early stages with courses of 15mg/m² daily orally for five days, have shown prolonged remissions. Combination chemotherapy is also commonly used in all stages of the disease.

Psoriasis:

Adults

It is recommended that a test dose of 5-10mg should be administered, one week prior to therapy to detect idiosyncratic adverse reactions.

In most cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, 10-25mg orally once a week and adjusted by the patient's response is recommended.

The use of methotrexate in psoriasis may permit the return to conventional topical therapy which should be encouraged.

Rheumatoid arthritis: Adults

It is recommended that a test dose of 5-10mg should be administered, one week prior to therapy to detect idiosyncratic adverse reactions.

In adults with severe, acute, classical or definite rheumatoid arthritis who are unresponsive or intolerant to conventional therapy, 7.5mg orally once weekly or divided oral doses of 2.5mg at 12 hour intervals for three doses (7.5mg) 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 20mg. 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 (see 4.4 Special Warning and Precautions for Use).

Children

Safety and effectiveness in children have not been established, other than in cancer chemotherapy.

4.3 Contraindications

Profound impairment of renal or hepatic function or haematological impairment. Liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease; and overt or laboratory evidence of immunodeficiency syndrome(s). Serious cases of anaemia, leucopenia, or thrombocytopenia. Methotrexate is contraindicated in pregnant patients. Because of the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contraindicated in women taking methotrexate. Patients with a known allergic hypersensitivity to methotrexate should not receive methotrexate.

4.4 Special warnings and precautions for use

The prescriber may specify the day of intake on the prescription.

Patients should be aware of importance of adhering to the once weekly intakes.

Warnings:

Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhoea, debility and in young children and the elderly. (See 4.2 Posology and Method of Administration).

Patients with pleural effusions or ascites should have these drained if appropriate before treatment or treatment should be withdrawn.

Symptoms of gastro-intestinal toxicity, usually first manifested by stomatitis, indicate that therapy should be interrupted otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Methotrexate has some immunosuppressive activity and therefore the immunological response to concurrent vaccination may be decreased. In addition, concomitant use of a live vaccine could cause a severe antigenic reaction.

Potentially fatal opportunistic infections, including Pneumocystis carinii pneumonia may occur with methotrexate therapy. When a patient presents with pulmonary symptoms the possibility of Pneumocystis carinii should be considered.

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 contract their doctor immediately should they develop persistent cough or dyspnoea.

Methotrexate should be withdrawn from patients with pulmonary symptoms and a through 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.

Precautions:

Methotrexate should only be used by clinicians who are familiar with the various characteristics of the drug and its mode of action. Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, a chest x-ray, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests. Patients undergoing therapy should be subject to appropriate supervision every 2-3 months so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Renal function and full blood counts should be closely monitored before, during and after treatment.

It is essential that the following laboratory tests are included regularly (every 2-3 months) in the clinical evaluation and monitoring of patients receiving methotrexate: complete haematological analysis, urinalysis, renal function tests, liver function tests and, when high doses are administered, determination of plasma levels of methotrexate.

Particular attention should be given to the appearance of liver toxicity which may occur without correlative changes in liver function tests. Treatment should not be instituted, or should be discontinued, if any abnormality in liver function tests or liver biopsy is present or develops during therapy. Such abnormalities should return to normal within two weeks, after which treatment may be recommenced at the discretion of the physician.

When to perform a liver biopsy in rheumatoid arthritis patients has not been established either in terms of a cumulative methotrexate dose or duration of therapy.

Pleuropulmonary manifestations of rheumatoid arthritis have been reported in the literature. In patients with rheumatoid arthritis, the physician should be specifically alerted to the potential for methotrexate induced adverse effects in the pulmonary system. Patients should be advised to contact their physicians immediately should they develop a cough or dyspnoea (see 4.8 Undesirable Effects).

Haematopoietic suppression caused by methotrexate may occur abruptly and with apparently safe dosages. Any profound drop in white-cell or platelet counts indicates immediate withdrawal of the drug and appropriate supportive therapy (see 4.8 Undesirable Effects). Patients should be advised to report all signs and symptoms suggestive of infection.

Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites or other effusions due to prolongation of serum half-life.

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 (5x 625mg tablets every three hours) or acetazolamide (500mg orally four times a day) is recommended as a preventive measure.

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.

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

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, sulphonamides, diuretics, hypoglycaemics, diphenylhydantoins, tetracyclines, chloramphenicol, p-aminobenzoic acid, and the acidic anti-inflammatory drugs, so causing a potential for increased toxicity when used concurrently. Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should generally be avoided, unless considered clinically justified, in which case the patient should be closely monitored.

Renal tubular transport is also diminished by probenecid and penicillins; use of methotrexate with these drugs should be carefully monitored.

NSAIDs should not be administered prior to, or concomitantly with, high dose methotrexate as fatal methotrexate toxicity has been reported. Caution is also advised when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and thereby may enhance its toxicity. It is recommended that methotrexate dosage be carefully controlled during treatment with NSAIDs.

Concomitant administration of folate antagonists, such as co-trimoxazole, have been reported to cause acute megaloblastic pancytopenia in rare instances. Methotrexate should be used with caution in patients taking drugs with an anti-folate potential, including nitrous oxide.

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

Existing data suggest that etretinate is formed from acitretin after ingestion of alcoholic beverages. However the formation of etretinate without concurrent alcohol intake cannot be excluded. Serum levels of methotrexate may be increased by etretinate and severe hepatitis has been reported following concurrent use.

4.6 Pregnancy and lactation

Methotrexate affects spermatogenesis and oogenesis during the period of its administration which may result in decreased fertility. To date, this effect appears to be reversible on discontinuing therapy. Conception should be avoided for at least three months after treatment with methotrexate has ceased. Patients receiving methotrexate and their partners should be advised appropriately.

Methotrexate has been shown to be teratogenic; it has been reported to cause foetal death and/or congenital abnormalities. Therefore, it is not recommended in women of childbearing potential unless the benefits can be expected to outweigh the considered risks. If this drug is used during pregnancy for antineoplastic indications, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.

Because of the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contraindicated in women taking methotrexate.

4.7 Effects on ability to drive and use machines

Methotrexate is not known to affect ability to drive or use machines.

4.8 Undesirable effects

The most common adverse reactions include ulcerative stomatitis, leucopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred. Others reported are eye irritation, malaise, undue fatigue, vasculitis, sepsis, arthralgia/myalgia, chills and fever, dizziness, loss of libido/impotence and decreased resistance to infection. 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 disseminated Herpes Simplex and cytomegalovirus infection, including cytomegaloviral pneumonia. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions for the various systems are as follows:

Integument:

Stevens-Johnson Syndrome, epidermal necrolysis, erythematous rashes, pruritus, urticaria, 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.

Haematopoietic:

Bone marrow depression is most frequently manifested by leucopenia, but thrombocytopenia, pancytopenia, anaemia, or any combination may occur. Infection or septicemia and haemorrhage from various sites may result. Hypogammaglobulinaemia has been reported.

Alimentary System:

Mucositis (most frequently stomatitis although gingivitis, pharyngitis and even enteritis, intestinal ulceration and bleeding) may occur. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon. Nausea, anorexia and vomiting and/or diarrhoea may also occur.

Hepatic:

Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or cirrhosis or death may occur, usually following chronic administration.

Urogenital System:

Renal failure and uraemia may follow methotrexate administration, usually in high doses. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.

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 4.6 Pregnancy and Lactation).

Pulmonary System:

Infrequently an acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Acute pulmonary oedema has also been reported after oral use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses.

In the treatment of rheumatoid arthritis, methotrexate induced lung disease is a potentially serious adverse drug reaction which may occur acutely at any time during therapy. It is not always fully reversible. Pulmonary symptoms (especially a dry, non productive cough) may require interruption of treatment and careful investigation.

Central Nervous System:

Headaches, drowsiness and blurred vision have occurred. Following low doses of methotrexate, transient subtle cognitive dysfunction, mood alteration, or unusual cranial sensations have been reported occasionally. Aphasia, paresis, hemiparesis, and convulsions have also occurred following administration of higher doses.

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.

Carcinogenesis and mutagenesis:

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. However, there is the potential for Non-Hodgkin’s lymphoma to develop through the use of methotrexate.

4.9 Overdose

Calcium folinate is the antidote for neutralising the immediate toxic effects of methotrexate on the haematopoietic system. It may be administered orally, intramuscularly, or by an intravenous bolus injection or infusion. In cases of accidental overdosage, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered within one hour and dosing continued until the serum levels of methotrexate are below 10^-7M. Other supporting therapy such as a 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.

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Methotrexate, a derivative of folic acid, belongs to the class of cytotoxic agents known as antimetabolites. It acts principally during the 'S' phase of cell division, by the competitive inhibition of the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate to tetrahydrofolate, a necessary step in the process of DNA synthesis and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, foetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are generally more sensitive to the effects of methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Clarification of the effect of methotrexate on immune activity and its relation to rheumatoid immunopathogenesis await further investigation.

In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.

5.2 Pharmacokinetic properties

In doses of 0.1mg (of methotrexate) per kg, methotrexate is completely absorbed from the G.I. tract; larger oral doses may be incompletely absorbed. 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.

Following oral doses of 0.06mg/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 0.037mg/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, e.g. in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress methotrexate clearance.

5.3 Preclinical safety data

There are no preclinical data of any relevance to the prescriber that are additional to those already included in other sections.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch

Colloidal anhydrous silica Magnesium stearate Lactose monohydrate Microcrystalline cellulose Potato starch

6.2    Incompatibilities

Not applicable

6.3    Shelf life

Three years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. Keep out the reach and sight of children.

6.5 Nature and contents of container

4, 8, 10, 12, 16, 20, 24, 28, 50 and 100 tablets in white polypropylene tablet containers sealed with a white polyethylene lid in cartons

6.6 Special precautions for disposal

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 a vesicant and should not cause harm if it comes into 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 folinate cover should be given.

Cytotoxic preparations should not be handled by pregnant staff.

Adequate care should be taken in the disposal of any unwanted product and containers. Any waste material may be disposed of by incineration. We do not make any specific recommendations with regard to the temperature of the incinerator.

7 MARKETING AUTHORISATION HOLDER

EBEWE Pharma Ges.m.b.H. Nfg. KG A-4866 Unterach Austria

MARKETING AUTHORISATION NUMBER(S)

PL 14510/0031

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/05/2005

10    DATE OF REVISION OF THE TEXT

09/11/2012