4.1. Therapeutic indications

- Active rheumatoid arthritis in adult patients.

- Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis.

4.2. Posology and method of administration

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risk of methotrexate therapy.

The prescriber should ensure that patients or their carers will be able to comply with the once weekly regimen. For doses not realisable/practicable with this strength another strength of this medicinal product is available.

Important warning about the dosage of methotrexate:

In the treatment of rheumatoid arthritis and psoriasis, methotrexate must only be taken once a week. Dosage errors in the use of methotrexate can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

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

Rheumatoid arthritis

The usual dose is 7.5 - 15 mg once weekly. The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 20 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 2.5–5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated. The usual dose is 7.5–15 mg taken once weekly.

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.

Use in elderly

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 occurs with increased age.

Use in patients with renal impairment – dose adjustments

Methotrexate is excreted to a significant extent by the kidneys, and therefore should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide intersubject pK variability.

Dose adjustments for methotrexate doses <100 mg/m2 in patients with renal impairment

Creatinine Clearance (ml/min)

% of dose to Administer

>60

100

30-59

50

<30

Methotrexate must not be administered

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 (see sections 4.3 and 4.4).

Use in a 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.

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.

Method of Administration

Oral.

4.3. Contraindications

• Significantly impaired hepatic function

• Significantly impaired renal function (creatinine clearance less than 30 ml/min)

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

• Alcoholism

• Severe acute or chronic infections and immunodeficiency syndrome

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

• Pregnancy and breast-feeding (see section 4.6)

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

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

• Methotrexate tablets should not be used concomitantly with drugs with antifolate properties (e.g. co-trimoxazole) (see section 4.5).

4.4. Special warnings and precautions for use

It should be emphasized to the patient that the recommended dose must be taken only once a week. The prescriber should specify the day of intake on the prescription. Patients should be instructed on the importance of adhering to the once-weekly intakes, and that mistaken daily use of the recommended dose has led to fatal toxicity (see Sections 4.2 and 4.9).

Methotrexate should be used with extreme caution in patients with haematological depression, renal impairment, diarrhoea, and ulcerative disorders of the GI tract and psychiatric disorders. Hepatic toxicity has been observed, usually associated with chronic hepatic disease. The administration of low doses of methotrexate for prolonged periods may give rise, in particular, to hepatic toxicity. Liver function should be closely monitored. If hepatic function abnormalities develop, methotrexate dosing should be suspended for at least two weeks. It is only appropriate to restart methotrexate provided the abnormalities return to normal and the re-exposure is deemed appropriate.

Particular care and possible cessation of treatment are indicated if stomatitis or GI toxicity occurs as haemorrhagic enteritis and intestinal perforation may result.

Reversible eosinophilic pulmonary reactions and treatment resistant, interstitial fibrosis may occur, particularly after long-term treatment.

Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination.

Renal function should be monitored by renal function tests and urinalyses. If serum creatinine levels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given (see section 4.2 and 4.3).

Treatment with methotrexate doses of >100 mg/m2 should not be initiated at urinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.

Renal lesions may develop if the urinary flow is impeded and urinary pH is low, especially if large doses have been administered.

Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and renal function are recommended.

As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.

If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.

If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate.

Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.

Haematopoietic suppression caused by Methotrexate may occur abruptly and with apparently safe dosages. 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 therapy should be withdrawn immediately and appropriate supportive therapy given (see Undesirable Effects section). Patients should be advised to report all symptoms or signs suggestive of infection.

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.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.

Liver function tests

Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies.

Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %. Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests. Liver biopsy should be considered on an individual basis taking into account the patient's comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment.

Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. Alcohol consumption should be avoided (see sections 4.3 and 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products.

Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases.

Fertility and reproduction

Fertility Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, and to cause impaired fertility, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy.

Teratogenicity – Reproductive risk

Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see section 4.6). The absence of pregnancy must be confirmed before methotrexate is used. If women of a sexually mature age are treated, effective contraception must be performed during treatment and for at least six months after.

For contraception advice for men see section 4.6.

If the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.

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 severe antigenic reaction.

Methotrexate should only be used by clinicians that 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. This will include a routine examination of lymph nodes and patients should report any unusual swelling to the doctor.

Patients receiving low-dose methotrexate should:

• Have a full blood count and renal and liver function tests before starting treatment. These should be repeated weekly until therapy is stabilised, thereafter patients should be monitored every 2-3 months throughout treatment.

• Patients should report all symptoms and signs suggestive of infection, especially sore throat.

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

The disappearance of methotrexate from plasma should be monitored, if possible. This is recommended in particular when high, or very high doses are administered in order to permit calculation of an adequate dose of leucovorin (folinic acid) rescue.

Patients with pleural effusions and ascites should be drained prior to initiation of methotrexate therapy or treatment should be withdrawn.

Pleuropulmonary manifestation of rheumatoid arthritis has 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 section 4.8, Undesirable effects).

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

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough), thoracic pain and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.

Methotrexate should be withdrawn from patient's 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.

Lung manifestations of RA and other connective tissue disorders are recognised to occur. In patients with RA, the physician should be specifically alerted to the potential for methotrexate induced adverse effects on the pulmonary system.

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

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Methotrexate is extensively protein bound and may displace, or be displaced by, other acidic drugs. The concurrent administration of agents such as diphenylhydantoins, acidic anti-inflammatory agents, salicylates, phenylbutazone, phenytoin, barbiturates, tranquilisers, oral contraceptives, amidopyrine derivatives, p-aminobenzoic acid, thiazide diuretics, doxorubicin, tetracyclines, probenecid, sulfinpyrazone or oral hypoglycaemics will decrease the methotrexate transport function of renal tubules, thereby reducing excretion and almost certainly increasing methotrexate toxicity.

Since probenecid and weak organic acids, such as “loop-diuretics” as well as pyrazols reduce tubular secretion, great caution should be exercised when these medicinal products are coadministered with methotrexate.

Concurrent use of other, potentially nephro- hemato or hepatotoxic agents (e.g. sulphasalazine, leflunomide and alcohol) should be avoided. Special caution should be exercised when observing patients receiving methotrexate therapy in combination with azathioprine or retinoids.

Methotrexate in combination with leflunomide can increase the risk for pancytopenia.

Enhancement of nephrotoxicity may be seen if high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).

Antibiotics, like penicillin, 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 gastrointestinal toxicity may occur.

Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broadspectrum antibiotics may reduce intestinal methotrexate absorption or interfere with the enterohepatic circulation, due to inhibition of the intestinal flora or suppression of bacterial metabolism.

Methotrexate dosage should be monitored if concomitant treatment with aspirin, ibuprofen or indometacin (NSAIDs) is commenced, as concomitant use of NSAID's has been associated with fatal methotrexate toxicity.

Hepatic, hematotoxic and nephrotoxic drugs should be avoided.

Vitamin preparations or other products containing folic acid or its derivatives may impair methotrexate efficacy.

Under (pre-) treatment with substances that may have adverse effects on the bone marrow (e.g. sulfonamides, trimethoprim-sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of marked haematopoietic disorders should be considered.

Co-administration of medicinal products which cause folate deficiency (e.g. sulfonamides, trimethoprim-sulfamethoxazole) can lead to increased methotrexate toxicity. Particular caution should therefore also be exercised in the presence of existing folic acid deficiency.

Acitretin (a treatment for psoriasis) is metabolised to etretinate. Methotrexate levels may be increased by etretinate and severe hepatitis has been reported following concomitant use.

Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.

Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the probability of severe haematoxic effects of methotrexate.

There is evidence that co-administration of methotrexate and omeprazole prolongs the elimination of methotrexate via kidneys. Co-administration of proton pump inhibitors such as omeprazole or pantoprazole can cause interactions. In combination with pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate metabolite, with myalgia and shivering, was reported in one case.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Excessive consumption of beverages containing caffeine or theophylline (coffee, soft drinks containing caffeine, black tea) should be avoided during methotrexate therapy since the efficacy of methotrexate may be reduced due to possible interaction between methotrexate and methylxanthines at adenosine receptors.

One should be aware of pharmacokinetic interactions between methotrexate, anticonvulsant medicinal products (reduced methotrexate blood levels), and 5-fluorouracil (increased t½ of 5--fluorouracil).

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, and stomatitis. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided.

Colestyramine can increase the non-renal elimination of methotrexate by interrupting the enterohepatic circulation.

Delayed methotrexate clearance should be considered in combination with other cytostatic medicinal products.

The application of procarbazine during high-dose methotrexate therapy increases the risk of impairment or renal function.

Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis.

Methotrexate increases plasma levels of mercaptopurine. Combinations of methotrexate and mercaptopurine may therefore require dose adjustment.

Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections (see section 4.3). On account of its possible effect on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to record the immune reaction). During methotrexate therapy concurrent vaccination with live vaccines must not be carried out (see sections 4.3 and 4.4).

Cytotoxic agents may impair absorption of phenytoin, which may decrease efficacy of phenytoin and increase the risk for exacerbation of convulsions. Risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin is possible.

Ciclosporin may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with risk of lymphoproliferation when the combination is used.

Particularly in the case of orthopaedic surgery where susceptibility to infection is high, a combination of methotrexate with immune-modulating medicinal products must be used with caution.

Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

4.6. Fertility, pregnancy and lactation

Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility. In humans, Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea. These effects appear to be reversible after discontinuation of therapy in most cases.

Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 6 months after cessation of methotrexate. Men should not donate semen during therapy or for 6 months following discontinuation of methotrexate.

Pregnancy

Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3).

If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development.

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.

Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in in disease-matched patients treated with drugs other than methotrexate.

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected.

When methotrexate was discontinued prior to conception, normal pregnancies have been reported.

Breast feeding

Patients should not breast feed whilst taking 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 may have minor or moderate influence on the ability to drive and use machines.

4.8. Undesirable effects

In general, the incidence and severity of side effects are considered to be-related to the dose, the dosing frequency, the method of administration and the duration of exposure.

Most adverse reactions are reversible if detected early. When adverse reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. This includes the use of calcium folinate (see sections 4.2 and 4.4). Methotrexate therapy should only be resumed with particular caution, after careful consideration of the need for treatment and with increased vigilance for the possible recurrence of toxicity.

Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome.

Most frequently observed adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently occurring adverse reactions are leukopenia, anaemia, thrombocytopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus.

The most relevant adverse reaction is suppression of the haematopoietic system and gastrointestinal disorders.

Adverse reactions for the various systems are as follows:

Skin and subcutaneous tissue disorders:

Exanthema, Stevens-Johnson Syndrome, toxic epidermal necrolysis, erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, erythema multiforme, onycholysis, increased pigmentation, petechia, allergic vasculitis, hidradenitis, alopecia, depigmentation, ecchymosis, telangiectasia, acne, furunculosis, painful damage to psoriatic lesions, skin ulceration, herpetiform eruptions of the skin, hyperpigmentation of the nails and acute paronychia.

Skin exfoliation / dermatitis exfoliative (frequency not known).

The recall phenomenon has been reported in both radiation and solar damaged skin. Lesions of psoriasis may worsen with concomitant UV therapy. Radiation dermatitis and sunburn may be “recalled”.

Blood and the lymphatic system disorders:

Megaloblastic anaemia, hematopoietic disorders, eosinophilia, lymphoproliferative disorder (partly reversible), lymphadenopathy, bone marrow depression (especially at high-dose of methotrexate) is most frequently manifested by thrombocytopenia (which are usually reversible), neutropenia, leukopenia, pancytopenia, agranulocytosis, anaemia, aplastic anaemia, immunosuppression, lymphoproliferative disorders frequency very rare) or any combination may occur. Infection or hypogammaglobulinaemia, haemorrhage from various sites. Bone marrow depression may lead to decreased resistance to infection and sepsis.

Gastrointestinal disorder:

Mucositis, stomatitis, gingivitis, hematemesis, melena, pancreatitis, enteritis, gastrointestinal ulceration (including oral ulcers) and bleeding, malabsorption, toxic megacolon. Dyspepsia, abdominal pain, anorexia, nausea, vomiting, diarrhoea.

Gastrointestinal disorders frequently require dosage adjustment. Ulcerative stomatitis and diarrhoea require interruption of therapy; otherwise hemorrhagic enteritis and death from intestinal perforation may occur.

Hepatobiliary disorders:

Hepatic toxicity resulting in increase of transaminases (ASAT, ALAT), alkaline phosphatase and bilirubin, decrease in serum albumin, acute hepatitis, periportal fibrosis, hepatic cirrhosis, hepatic failure, fatty degeneration of liver, reactivation of chronic hepatitis or death.

Renal and urinary disorders:

Renal failure, ulceration of the urinary bladder, disturbed micturition, oliguria, haematuria, dysuria, anuria, proteinuria, electrolyte disturbance, nephropathy.

Respiratory, thoracic and mediastinal disorders:

Pneumonia, acute or chronic interstitial alveolitis/pneumonia which can be fatal and is often associated with eosinophilia, acute pulmonary oedema, interstitial/pulmonary fibrosis, chronic interstitial obstructive pulmonary disease, pharyngitis, pleurisy, non-productive cough, dyspnoea, pleural effusion, bronchial asthma, epistaxis, respiratory paralysis.

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.

Epistaxis (frequency not known) has been reported. Pulmonary alveolar haemorrhage (frequency not known) has been reported for methotrexate used in rheumatologic and related indications.

Nervous System disorder:

Headaches, fatigue, drowsiness, dizziness, vertigo, lethargy, aphasia, irritability, hemiparesis, paresis, convulsions, encephalopathy/ leukoencephalopathy.

Leukoencephalopathy has been reported especially following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Cerebral oedema, transient subtle cognitive dysfunction, dysarthria, unusual cranial sensations.

Pain, muscular asthenia or paraesthesia/hypoaesthesia (frequency very rare), changes in sense of taste (metallic taste), meningism, acute aseptic meningitis, paralysis.

Psychiatric disorders:

Depression, confusion, Mood alterations, insomnia, psychoses.

Cardiac disorder:

Percardial effusion, Pericarditis pericardial tamponade.

Vascular disorders:

Thromboembolic events (arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolus), vasculitis, hypotension.

Eye disorders:

Conjunctivitis, blurred/impaired vision, retinopathy.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

Lymphoma, which can be reversible, Methotrexate may trigger tumour lysis syndrome in patients with rapidly growing tumour.

Reproductive system and breast disorder:

Gynecomastia, decreased libido/impotence, defective oogenesis or spermatogenesis, transient oligospermia, infertility, menstrual dysfunction, vaginal bleeding, vaginal ulceration, inflammation of the vagina, vaginal discharge.

Infections and infestations:

Respiratory or cutaneous bacterial infections, herpes zoster infections, opportunistic infections, Pneumocystis carinii/jiroveci pneumonia and other lung infection, reactivation of inactive chronic infection.s

Musculoskeletal, connective tissue and bone disorders:

Osteoporosis, stress fractures, arthralgia/myalgia, increased rheumatic nodules. Osteonecrosis of jaw (frequency not known) (secondary to lymphoproliferative disorders).

Endocrine disorders:

Diabetes mellitus.

Immune system disorders:

Allergic reaction, anaphylactic reaction, anaphylactic shock.

Ear and labyrinth disorders:

Tinnitus.

General disorders:

Fever, chills, wound healing impairment, asthenia.

Oedema (frequency not known).

Other:

Increased risk of toxic reactions in radiotherapy (soft tissue necrosis, osteonecrosis).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

The toxicity of methotrexate affects mainly the haematopoietic organs. Calcium folinate neutralises effectively the immediate toxic effects of methotrexate. Parenteral calcium folinate therapy should be started within one hour after the administration of methotrexate. The dose of calcium folinate should be at least as high as the dose of methotrexate received by the patient.

Symptoms of an overdose are mainly the same as the undesirable effects, but stronger.

Leucovorin is a specific antidote for methotrexate and, following accidental overdosage, should be administered within one hour at a dosage equal to, or greater than, the methotrexate dose. It may be administered by i.v. bolus or infusion. Further doses may be required. The patient should be observed carefully and blood transfusions, renal dialysis and reverse barrier nursing may be necessary.

In post-marketing experience, overdose with methotrexate has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose has also been reported.

Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate. In these cases, symptoms that have been commonly reported are hematological and gastrointestinal reactions. For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some cases, no symptoms were reported. There have been reports of death following chronic overdose in the self-administered dosage for rheumatoid arthritis and psoriasis (see Sections 4.2 and 4.4). In these cases, events such as sepsis or septic shock, renal failure, and aplastic anaemia were also reported.

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

Treatment measures for methotrexate overdosage can be discontinued when the serum methotrexate level has fallen below the level of 5x10-8 M (10) (see section 4.4).