SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methotrexate Orion 10 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains methotrexate disodium equivalent to 10 mg methotrexate (anhydrous).

Excipient with known effect: 311.2 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Yellow, round, uncoated, flat tablet, scored and engraved with ORN 59 on one side, diameter 10.5 mm.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Antirheumatic: Active rheumatoid arthritis in adult patients Antipsoriatic: Severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients Cytostatic: Maintenance therapy in acute lymphoblastic leukemia.

4.2 Posology and method of administration

Methotrexate should only be prescribed by physicians with experience in the various properties of the medicinal product and its mode of action.

It must be explicitly pointed out to the patient that for the therapy of rheumatic diseases or diseases of the skin Methotrexate is administered only once a week.

It is recommended to specify a certain day of the week as “the day for taking Methotrexate” on the prescription.

Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration (see section 5.2 and 4.4).

Rheumatoid arthritis

The usual dose is 7.5 - 15 mg once weekly. The planned weekly dose may be administered in three divided doses during 24 hours (at 12 hours’ interval).

The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 25 mg. Thereafter the dose should be reduced to the lowest possible effective dose which in most cases is achieved within 6 weeks.

Psoriasis

Before starting treatment it is advisable to give the patient a test dose of 2.55.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated. The usual dose is 7.515 mg taken once weekly. The planned weekly dose administered as three divided doses over 24 hours. As necessary, the total weekly dose can be increased up to 25 mg. Thereafter the dose should be reduced to the lowest effective dose according to therapeutic response which in most cases is achieved within 4 to 8 weeks.

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.

Cytostatic

Oral administration of methotrexate at doses of up to 30 mg/m is possible but higher doses should be administrated parenterally.

Children

Methotrexate 15 mg/m should be given orally once weekly for maintenance of drug-induced remissions.

The use in children below 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population (see section 4.4).

Special populations

Use in elderly patients

Methotrexate should be used with extreme caution in elderly patients, a dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occur with increased age.

Patients with renal impairment:

Methotrexate should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:

Creatinine clearance    Dose

(ml/min)

> 60    100 %

30-59    50 %

< 30    Methotrexate must not be used

See section 4.3

Patients with hepatic impairment:

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. Methotrexate is contraindicated in patients with significantly impaired hepatic function, see section 4.3.

Use in patient with a third distribution space (pleural effusions, ascites)

As the half-life of methotrexate can be prolonged to 4 times the normal length in patients who possess a third distribution space dose reduction or, in some cases, discontinuation of methotrexate administration may be required (see section 5.2 and 4.4).

Special note

If changing the oral application to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration.

Folic acid or folinic acid supplementation may be considered according to current treatment guidelines.

4.3 Contraindications

-    Hypersensitivity to methotrexate or to any of the excipients listed in section 6.1

-    Significantly impaired    hepatic function

-    Alcoholism

-    Significantly impaired    renal function

Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia Severe acute or chronic infections and immunodeficiency syndromes Pregnancy and breast-feeding

During methotrexate therapy concurrent vaccination with live vaccines must not be carried out.

4.4 Special warnings and precautions for use

Warnings

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Concomitant administration of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drug, 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 constant supervision.

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 undertaken to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Deaths have been reported associated with the use of methotrexate in the treatment of psoriasis.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

The Patients should be informed clearly that in the treatment of psoriasis and rheumatoid arthritis the administration is in most cases once weekly. Patients should be aware of the importance of adhering to the once weekly intakes and that wrong daily administration can result in severe toxic reactions. The prescriber may specify the day of intake on the prescription.

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.

Methotrexate may be hepatotoxic, particularly at high doses 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.

Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13 - 20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be exercised in Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide).

There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications. In case of longer-term treatment of severe forms of psoriasis with methotrexate, liver biopsies should be performed on account of the hepatotoxic potential.

Patients with risk factors

These primarily include:

-    anamnestic alcohol abuse

-    persistent increase in liver enzymes

-    anamnestic hepatopathy including chronic hepatitis B or C

-    familial anamnesis with hereditary hepatopathy

and secondarily (with possibly lower relevance):

-    diabetes mellitus

-    adiposity

-    anamnestic exposure to hepatotoxic medicines or chemicals.

The need of liver biopsy should be evaluated case by case and national recommendations should be followed.

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 patients must not receive methotrexate (see section 4.6).

Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. The dose of methotrexate in patients with renal impairment should be reduced. 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.

Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

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.

Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. Vaccination with live vaccines should be avoided during therapy.

The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Special attention should be paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) because of their potential activation.

A chest X-ray is recommended prior to initiation of methotrexate therapy.

Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

In the treatment of rheumatoid arthritis, treatment with acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAID) as well as small-dose steroids can be continued. One has to take into consideration, however, that coadministration of NSAIDs and methotrexate may involve an increased risk of toxicity. The steroid dose can be reduced gradually in patients who exhibit therapeutic response to methotrexate therapy.

Interaction between methotrexate and other antirheumatic agents, such as gold, penicillamin, hydroxychloroquine, sulphasalazine or other cytotoxic agents, have not been studied comprehensively, and coadministration may involve an increased frequency of adverse reactions.

Concomitant administration of folate antagonists such as trimethoprim/ sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

If acute methotrexate toxicity occurs, patients may require folinic acid. Precautions

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and a bone marrow function should be made by history, physical examination and laboratory tests.

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.

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 section 4.6).

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. Pre-treatment and periodic haematological studies are essential for the safe use of methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur without warning when a patient is on an apparently safe dose, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate: 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.

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.

Encephalopathy/Leukoencephalopathy have been reported in oncologic patients receiving methotrexate therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.

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

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol, hepatotoxic medicinal products, haematotoxic medicinal products The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4). Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be monitored with special care. The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine).

The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with methotrexate.

Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of hepatotoxicity.

Be aware of pharmacokinetic interactions between methotrexate, anticonvulsant drugs (reduced methotrexate blood levels), and 5-fluorouracil (increased t/ of 5-fluorouracil).

Antibiotics

Antibiotics, like penicillins, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur.

In addition orally administered antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation of methotrexate, by inhibition of the intestinal flora or suppression of the bacterial metabolism.

Medicinal products with high plasma protein binding Methotrexate is plasma protein bound and may be displaced by other protein bound drugs such as salicylates, hypoglycaemic agents, diuretics, sulphonamides, diphenylhydantoin, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, which can lead to increased toxicity when used concurrently.

Probenecid, weak organic acids, pyrazoles and non-steroidal antiinflammatory agents (NSAID)

Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed inducing higher haematological toxicity. Great caution should be exercised when these medicinal products are coadministered with methotrexate. NSAID preparations must not be given prior to or concomitantly with the high doses of methotrexate. Concomitant administration of NSAIDs and methotrexate at high doses has reportedly elevated and prolonged serum methotrexate levels, resulting in deaths from severe haematological and gastrointestinal toxicity. There is also a possibility of increased toxicity when low dose methotrexate and non-steroidal antiinflammatory medicinal products or salicylates are combined.

Medicinal products with adverse reactions on the bone marrow In the case of medication with medicinal products, which may have adverse reactions on the bone marrow (e.g. sulfonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation.

Medicinal products which cause folate deficiency

The concomitant administration of products which cause folate deficiency (e.g. sulfonamides, trimethoprim-sulfamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency.

Products containing folic acid or folinic acid

Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.

Other antirheumatic medicinal products

An increase in the toxic effects of methotrexate is, in general, not to be expected when methotrexate is administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, ciclosporin).

Sulfasalazine

Although the combination of methotrexate and sulfasalazine can cause undesirable effects, e.g. folate-deficiency anaemias, due to the inhibition of folic acid synthesis through sulfasalazine, such undesirable effects have only been observed in rare individual cases.

Mercaptopurine

Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.

Proton-pump inhibitors

A concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate with myalgia and shivering was reported in one case.

Theophylline

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Beverages containing caffeine or other methylxanthines An excessive consumption of beverages containing caffeine or other methylxanthines (coffee, caffeine-containing soft drinks, black tea) should be avoided during methotrexate therapy, because they may reduce efficacy of methotrexate.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use of methotrexate is contraindicated throughout pregnancy (see section 4.3), since there is evidence of a teratogenic risk in humans (craniofacial, cardiovascular and extremital malformations) and in several animal species (see section 5.3).

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. pregnancy test, prior to initiating therapy.

Women must not become pregnant during and at least 6 months after treatment with methotrexate and must therefore practise an effective form or contraception.

If, nevertheless, pregnancy occurs during this period, medical advice should be given regarding the risk of harmful effects on the child associated with treatment.

As methotrexate may be genotoxic, women who wish to become pregnant are advised to consult a genetic councelling centre, if possible, already prior to therapy.

Breastfeeding

As methotrexate passes into breast milk and may cause toxicity in nursing infants, treatment is contraindicated during the lactation period (see section 4.3). Breast-feeding is therefore to be stopped prior to treatment.

Fertility

Male fertility

Methotrexate may be genotoxic. Men treated with methotrexate are therefore recommended not to father a child during treatment and up to 6 months afterwards. Since treatment with methotrexate can lead to severe and possibly irreversible disorders in spermatogenesis, men should seek advice about the possibility of sperm preservation before starting therapy.

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.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving methotrexate.

4.7 Effects on ability to drive and use machines

Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with methotrexate which have minor or moderate influence on the ability to drive and use machines.

4.8 Undesirable effects

Generally the frequency and severity of adverse reactions are dependent of the size of the dose, the dosing frequency, the method of administration and the duration of exposure.

If adverse reactions occur, the dose should be reduced or therapy discontinued and necessary corrective therapeutic measures undertaken, such as administration of calcium folinate (see sections 4.2 and 4.4).

The most common adverse reactions of methotrexate are bone marrow suppression and mucosal damage which manifest as ulcerative stomatitis, leukopenia, nausea and other gastrointestinal disorders. These adverse reactions are generally reversible and corrected in about two weeks after the single dose of methotrexate has been reduced or dose interval increased and/or calcium folinate is used. Other frequently occurring adverse reactions include e.g. malaise, abnormal fatigue, chills and fever, dizziness and reduced immunity to infections.

Methotrexate causes adverse reactions most at high and frequently repeated doses, e.g. in the treatment of cancer diseases. Adverse reactions reported on methotrexate are given below according to organ systems.

Although very rare, anaphylactic reactions to methotrexate have been reported. 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).

Adverse reactions for the various systems are as follows:

The frequencies of the adverse reactions are classified as follows: Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data)._

	Common	Uncommon	Rare	Very rare	Not known
Psychiatric disorders			Depression Confusion
Nervous system disorders	Headache Dizziness Fatigue Paraesthesia in the extremities		Hemiparesis	Irritation Dysarthria Aphasia Lethargy
Eye disorders				Conjunctivitis Blurred vision
Cardiac disorders				Pericardial effusion Pericarditis
Vascular disorders		Nosebleed	Hypotension Thromboembol ism	Vasculitis
Respiratory, thoracic and mediastinal disorders		Pneumonitis Interstitial pneumonitis (can be fatal) Interstitial fibrosis	Dyspnoea Pharyngitis2	Pneumocystis carinii -pneumonia Chronic interstitial obstructive lung disease Pleuritis Dry cough	Alveolitis
Gastrointestina l disorders3	Stomatitis Anorexia Nausea Vomiting Diarrhoea		Gingivitis Gastrointestinal ulcerations and haemorrhage Enteritis	Haematemesis
Hepatobiliary disorders	Elevated transaminase concentrations		Hepatotoxicity Periportal fibrosis Liver cirrhosis Acute hepatitis
Skin and subcutaneous tissue disorders	Erythematous rash Alopecia	Pruritus Stevens- Johnsons syndrome Toxic epidermal necrolysis	Photohypersens itivity Acne Depigmentatio n Urticaria Erythema multiforme Painful damage to psoriatic lesion Skin ulceration	Telangiectasia Furunculosis Ecchymoses
Musculoskeleta l and connective tissue disorders			Osteoporosis Arthralgia Myalgia Accelerated rheumatic nodulosis
Renal and urinary disorders		Renal insufficiency Nephropathy		Dysuria Azotaemia Cystitis Haematuria
Pregnancy,					Miscarriage,

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms:

Toxicity of methotrexate mainly affects the haematopoietic and gastrointestinal systems. Symptoms include leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, bone marrow depression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and gastrointestinal bleeding. Some patients showed no signs of overdose.

There are reports of death due to sepsis, septic shock, renal failure and aplastic anaemia.

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.

Treatment:

Calcium folinate is the specific antidote for neutralising the toxic undesirable effects of methotrexate.

In cases of accidental overdose, a dose of calcium folinate equal to or higher than the offending dose of methotrexate should be administered intravenously or intramuscularly within one hour

Observation of serum methotrexate concentrations is relevant in determining the right dose of calcium folinate and the duration of the therapy.

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

Pharmacotherapeutic groups:

Other immunosuppressants, ATC code: L04AX03

Methotrexate (4-amino-10-methylfolic acid) is a folic acid antagonist which inhibits the reduction of folic acid leading to decreased cellular proliferation. Methotrexate enters the cell through an active transport mechanism of reduced folates. As a result of polyglutamylation of methotrexate caused by the folylpolyglutamate synthetase enzyme, the duration of the cytotoxic effect of the drug substance in the cell increases. Methotrexate is a phase-specific substance the main action of which is directed to the S-phase of cell mitosis. It acts generally most effectively on actively proliferating tissues, such as malignant cells, bone marrow, foetal cells, skin epithelium, oral and intestinal mucosa as well as urinary bladder cells. As the proliferation of malignant cells is faster than that of most normal cells, methotrexate can slow down the proliferation of malignant cells without causing irreversible damage to normal tissue.

Calcium folinate is a folinic acid which is used to protect normal cells from the toxic effects of methotrexate. Calcium folinate enters the cell through a specific transport mechanism, is converted in the cell into active folates and reverses the inhibition of the synthesis of precursors of DNA and RNA.

5.2 Pharmacokinetic properties

Absorption

The effect of orally administered methotrexate is dependent on the size of the dose. Peak concentrations in serum are reached within 1 - 2 hours. Generally a dose of methotrexate of 30 mg/m² or less is absorbed rapidly and completely. The bioavailability of orally administered methotrexate is high (80-100%) at doses of 30 mg/m² or less. At doses above 30 mg/m² absorption becomes nonlinear and absorption at doses exceeding 80 mg/m is incomplete.

Distribution

Approximately 50 % of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations in the form of polyglutamates are found in the liver, kidneys and spleen in particular, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts.

Biotransformation

Approx. 10 % of the administered methotrexate dose is metabolised in the liver. The principle metabolite is 7-hydroxymethotrexate.

Elimination

Excretion takes place, mainly in unchanged form, primarily via glomerular filtration and active secretion in the proximal tubule.

Approx. 5 - 20 % methotrexate and 1 - 5 % 7-hydroxymethotrexate are eliminated biliary with pronounced enterohepatic circulation

The terminal half-life is on average 6 - 7 hours and demonstrates considerable variation (3 - 17 hours). The half-life can be prolonged to 4 times the normal length in patients who possess a third distribution space (pleural effusion, ascites).

Special populations

In the case of renal insufficiency, elimination is delayed significantly.

5.3 Preclinical safety data

Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. Animal studies show that methotrexate impairs fertility, and is embryo- and foetotoxic. Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys no malformations occurred. Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes cromosomal aberrations in animal cells and in human bone marrow cells, but the clinical significance of these findings has not been established. Rodent carcinogenicity studies do not indicate an increased incidence of tumours.

6.1 List of excipients

Lactose monohydrate Cellulose, microcrystalline Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Keep the tablet container /blister in the outer carton in order to protect from light.

6.5 Nature and contents of container

HDPE tablet container with child-resistance polypropylene (PP) closure. 10 mg: 10, 15, 25, 50 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Proper procedures for safe handling of cytotoxic agents should be administered. Disposable gloves should be used when handling methotrexate tablets. Pregnant women should avoid handling methotrexate tablets, if possible

Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

MARKETING AUTHORISATION HOLDER

Orion Corporation Orionintie 1 FI-02200 Espoo Finland

8    MARKETING AUTHORISATION NUMBER(S)

PL 27925/0089

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/08/2016

10    DATE OF REVISION OF THE TEXT

05/08/2016