This information is intended for use by health professionals

1. Name of the medicinal product

Methotrexate 2.5 mg Tablets

2. Qualitative and quantitative composition

Methotrexate 2.5 mg tablet

Each tablet contains methotrexate 2.5 mg.

Excipient with known effect

Each tablet contains 12.50 mg lactose (as lactose monohydrate).

Each tablet contains 0.076 mg sodium

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

Methotrexate 2.5 mg tablet

Yellow, circular, biconvex uncoated tablets with dimension of 4.50 mm ± 0.20 mm plain on both sides

4. Clinical particulars
4.1 Therapeutic indications

• Active rheumatoid arthritis in adult patients.

• 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.

4.2 Posology and method of administration

Important warning about the dosage Methotrexate tablets (methotrexate):

In the treatment of rheumatic diseases or diseases of the skin requiring dosing once a week, Methotrexate tablets (methotrexate) must only be taken once a week. Dosage errors in the use of Methotrexate tablets (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

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

It must be explicitly pointed out to the patient that methotrexate is applied only once a week.

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

Rheumatoid arthritis

The usual dose is 7.5 - 15 mg once weekly. The planned weekly dose may be administered in three divided doses over 24 hours. 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. 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.

Graphic representation as an illustration on the taking of tablets in the inflammatory indications for adults

Rheumatoid arthritis and psoriasis

The initial dose in adults is 3X 2.5 mg tablets (7.5 mg) once a week. Therefore, the packaging of Methotrexate 2.5 mg tablets containing 24 tablets covers treatment for 8 weeks, the distribution is given as below:

Initial dosage: 3X 2.5 mg tablets per week (7.5 mg per week)

If the dose had to be increased, an additional tablet (2.5 mg) per week would be added, that is, 4X2.5 mg tablets per week. In this case, the packaging of Methotrexate 2.5 mg tablets with 24 tablets will cover 6 weeks of treatments, the distribution is given as below.

Increased dosage: 4 X 2.5 mg tablets per week (10 mg per week)

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 occur with increased age.

Renal impairment

Methotrexate should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The dose should be adjusted as follows:

Creatinine clearance (ml/min)

≥ 60

30 – 59

< 30

Dose

100 %

50 %

Methotrexate must not be used

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.

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 (see section 4.6)

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

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

4.4 Special warnings and precautions for use

Dosing in the treatment of rheumatoid arthritis, psoriasis and psoriatic arthritis:

The patients should be informed clearly that in the treatment of psoriasis and rheumatoid arthritis the administration is once weekly. The prescriber should specify the day of intake on the prescription.

The prescriber should make sure patients understand that Methotrexate tablets (methotrexate) should only be taken once a week.

Patients should be instructed on the importance of adhering to the once-weekly intakes.

Warnings

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

Patients must be appropriately monitored during treatment so that signs of possible toxic effects or adverse reactions can be detected and evaluated with minimal delay.

Because of the possibility of severe or even fatal toxic reactions, patients should be extensively informed by the treating doctor of the risks involved (including early signs and symptoms of toxicity) and the recommended safety measures. Patients should be informed that they must notify the doctor immediately if any symptoms of an overdose occur and that the symptoms of the overdose need to be monitored (including regular laboratory tests).

Doses exceeding 20 mg week can be associated with a substantial increase in toxicity, especially bone marrow depression.

Because of the delayed excretion of methotrexate in patients with impaired kidney function, they should be treated with particular caution and only with low doses of methotrexate (see sections 4.2 and 4.3).

Methotrexate should be used only with great caution, if at all, in patients who have a significant liver disease, particularly if this is/was alcohol-related (see sections 4.2 and 4.3).

Concomitant administration of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drug, e.g. leflunomide) is not advisable.

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. Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation (including chest X-ray) undertaken to exclude infection and tumours. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Methotrexate-induced lung diseases such as pneumonitis can occur acutely and at any time during treatment, are not always completely reversible and have already been observed at all doses (including low doses of 7.5 mg/week).

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.

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.

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). Further research is needed to establish whether serial liver function tests or determinations of propeptide of type III collagen are appropriate for detecting hepatotoxicity.

There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications. For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. The need of liver biopsy should be evaluated case by case and national recommendations should be followed. This assessment should differentiate between patients with no risk factors and patients with risk factors such as excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of inheritable liver disease, diabetes mellitus, obesity, and history of significant exposure to hepatotoxic drugs or chemicals and prolonged methotrexate treatment or cumulative doses of 1.5 g or more.

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.

Renal function should be closely monitored before, during and after treatment by renal function tests and urinalysis. If serum creatinine is increased, the dose should be reduced. As methotrexate is predominantly excreted via the renal route, increased concentrations can be expected in cases of renal impairment, which may result in severe adverse reactions. In cases of possible renal impairment (e.g. in elderly patients), closer monitoring is required. This particularly applies to the co-administration of medicinal products which affect methotrexate excretion, cause kidney damage (e.g. NSAIDs) or can potentially lead to haematopoietic disorders. In patients with impaired renal function, concomitant administration of NSAIDs is not recommended. Dehydration may also potentiate the toxicity of methotrexate.

Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur. Following the occurrence of haematemesis, black coloured stools or blood in the stools, treatment must be discontinued.

In addition other conditions leading to dehydration such as emesis, diarrhoea or stomatitis can increase the toxicity of methotrexate due to elevated levels of the active substance. In these cases use of methotrexate should be interrupted until symptoms cease. It is important to determine any increase in active substance levels within 48 hours of therapy, otherwise irreversible methotrexate toxicity may occur.

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, sulfasalazine 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/ sulfamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

If acute methotrexate toxicity occurs, patients may require folinic acid. In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid supplementation may reduce methotrexate toxicity, such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver enzymes.

It is recommended to check levels of vitamin B12 prior to initiating folic acid supplementation, particularly in adults aged over 50 years, as folic acid intake may mask a vitamin B12 deficiency. Since cases of encephalopathy/leukoencephalopathy have occurred in cancer patients treated with methotrexate, this cannot be ruled out either for patients with non-cancer indications.

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.

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, sulfonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulfonamides, 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/history of infection, peptic ulcer, ulcerative colitis, debility, and old age. Use in patients with active gastrointestinal ulcer disease is contraindicated. 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.

Radiation induced dermatitis and sun-burn can reappear under methotrexate therapy (recall-reaction). Psoriatic lesions can exacerbate during UV-irradiation and simultaneous administration of methotrexate.

Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell's syndrome) or Stevens-Johnson syndrome have been reported after single or multiple doses of methotrexate.

Excipients

Lactose

The tablet contains lactose. Patient with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

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

After absorption methotrexate binds partly to serum albumin. Certain medicinal products (e.g. salicylates, sulphonamides, phenylbutazone, phenytoin, barbiturates, tranquilisers, oral contraceptives, amidopyrine derivatives, p-aminobenzoic acid, thiazide diuretics, oral hypoglycaemics and doxorubicin) decrease this binding. In such instances the toxicity of methotrexate may increase when coadministered. 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.

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 gastro-intestinal toxicity may occur.

Oral antibiotics, such as tetracycline, chloramphenicol, and non-absorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.

Coadministration of other, potentially nephro, hemato - and hepatotoxic agents (e.g. sulfasalazine, leflunomide and alcohol) with methotrexate 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.

NSAIDs should not be administered before or concurrently with high-dose methotrexate. Concomitant use of some NSAIDs and high-dose methotrexate has been reported to increase and prolong the serum methotrexate concentration in serum and to increase gastrointestinal and haematological toxicity. When using smaller doses of methotrexate, these medicinal products have been found in animals to decrease the tubular secretion of methotrexate and possibly to increase its toxicity. In addition to methotrexate, patients with rheumatoid arthritis have generally been treated, however, with NSAIDs with no problems. It should be noted, however, that the doses of methotrexate used in the treatment of rheumatoid arthritis (7.5 - 15 mg/week) are slightly lower than those used for psoriasis and that higher doses can result in unexpected toxicity.

Vitamin preparations or other products containing folic acid or its derivatives may change the response to methotrexate.

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

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

Bone marrow suppression and reduced folate concentrations have been reported when triamterene and methotrexate were coadministered.

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

There is evidence that coadministration of methotrexate and omeprazole prolongs the elimination of methotrexate via the kidneys. Coadministration 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).

However, 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.

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

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).

Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or lose of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

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

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 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.

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

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.

4.6 Fertility, pregnancy and lactation

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.

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

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.

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

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). 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.

The most serious adverse reactions of methotrexate includes 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 reported on methotrexate are given below according to organ systems.

The frequencies of the adverse reactions are classified as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Very Common

Common

Uncommon

Rare

Very Rare

Not known

Infections and infestations

Infections

Opportunistic infections

Herpes zoster

Sepsis

Sepsis resulting in death

Reactivation of inactive chronic infection

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

Lymphoma1

Blood and lymphatic system disorders

Leucopaenia

Bone marrow depression

Agranulocytosis

Thrombocytopaenia

Anaemia

Hematopoietic disorders

Megaloblastic anemia

Hypo-gammaglobulinaemia, Lymphoproliferative disorders (see “description” below the table)

Lymphadenopathy

Neutropenia

Aplastic anemia

Pancytopenia, eosinophilia

Immune system disorders

Anaphylactic-type reaction

Immuno-suppression

Anaphylactic shock

Allergic reactions

Endocrine disorders

Diabetes mellitus

Psychiatric disorders

Depression

Confusion

Mood alterations

Insomnia

Psychoses

Nervous system disorders

Headache

Drowsiness

Dizziness

Fatigue

Vertigo

Hemiparesis

Paresis

Irritation

Dysarthria

Aphasia

Lethargy

Cerebral oedema, Transient subtle cognitive dysfunction

Unusual cranial sensations

Convulsions

Pain, muscular asthenia or paraesthesia in the extremities

Changes in sense of taste (metallic taste)

Meningism

Acute aseptic meningitis

Paralysis

Encephalopathy/ Leuko-encephalopathy

Eye disorders

Conjunctivitis

Blurred vision

Impaired vision

Retinopathy

Ear and labyrinth disorders

Tinnitus

Cardiac disorders

Pericarditis

Pericardial effusion

Pericardial tamponade

Vascular disorders

Hypotension

Thromboembolism

Vasculitis

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Interstitial pneumonitis

Interstitial/ pulmonary fibrosis

Dyspnoea

Pharyngitis2

Respiratory paralysis

Pneumocystis jiroveci – pneumonia and other lung infections

Chronic interstitial obstructive lung disease

Pleuritis

Pleural effusion

Dry cough

Interstitial alveolitis4

Epistaxis

Bronchial asthma

Pulmonary alveolar haemorrhage

Gastrointestinal disorders3

Stomatitis

Dyspepsia

Anorexia

Nausea

Vomiting

Abdominal pain

oral ulcer

Diarrhoea

Gingivitis

Gastrointestinal ulcerations and haemorrhage

Enteritis

Melaena

Haematemesis

Toxic megacolon

Pancreatitis

Hepatobiliary disorders

Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and bilirubin)

Decrease in serum albumin

Fatty degeneration of the liver

Hepatotoxicity

Periportal fibrosis

Liver cirrhosis

Acute hepatitis

Reactivation of chronic hepatitis

Hepatic failure

Skin and subcutaneous tissue disorders

Erythematous rash

Alopaecia

Exanthema

Pruritus

Stevens-Johnson´s syndrome

Toxic epidermal necrolysis

Herpetiform eruptions of the skin

Increased skin pigmentation

Photohypersensitivity

Acne

Depigmentation

Urticaria

Erythema multiforme

Painful damage to psoriatic lesion

Skin ulceration

Onycholysis

Increased nail pigment changes

Petechiae

Allergic vasculitis

Radiation dermatitis and sunburn may be “recalled”

Telangiectasis

Furunculosis

Ecchymoses

Hidradenitis

Acute paronchynia

Musculoskeletal and connective tissue disorders

Osteoporosis

Arthralgia

Myalgia

Increased rheumatic nodules

Stress fracture

Osteonecrosis of jaw (secondary to lymphoproliferative disorders)

Renal and urinary disorders

Renal insufficiency

Nephropathy

Inflammation and ulceration of the urinary bladder

Disturbed micturition

Dysuria

Oliguria

Anuria

Electrolyte disturbances

Azotaemia

Haematuria

Proteinuria

Pregnancy, puerperium and perinatal conditions

Miscarriage, fetal damages

Reproductive system and breast disorders

Vaginal

inflammation and ulceration

Decreased libido

Impotence

Menstrual disorders

Formation of defective oocytes or sperm cells

Transient oligospermia, infertility

Vaginal bleeding

Vaginal

discharge

Gynaecomastia

General disorders and administration site conditions

Chills

Fever

Wound-healing impairment

Asthenia

Injury, poisoning and procedural complications

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

The psoriatic lesions may get worse from simultaneous exposure to methotrexate and ultraviolet radiation.

1. Can be reversible (see 4.4).

2. See section 4.4.

3. Gastrointestinal severe adverse reactions require often dose reduction. Ulcerative stomatitis and diarrhoea require discontinuation of methotrexate therapy because of the risk of ulcerative enteritis and fatal intestinal perforation.

4. Can be fatal and is often associated with eosinophilia.

Description of selected adverse reactions

Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and other lymphoproliferative disorders which subsided in a number of cases once treatment with methotrexate had been discontinued.

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

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 haematological and gastrointestinal reactions.

The toxicity of methotrexate affects mainly the haematopoietic organs. Calcium folinate neutralises effectively the immediate haematopoietic 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.

Massive overdose requires hydration and alkalinisation of the urine to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Haemodialysis or peritoneal dialysis has not been found to affect the elimination of methotrexate. Instead, effective clearance of methotrexate has been achieved by intermittent haemodialysis using a so-called “high-flux” dialysator.

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants; other immunosuppressants ATC code: L04AX03

Methotrexate (4-amino-10-methylfolic acid) is a folic acid antagonist which inhibits the reduction of folic acid and increase of tissue cells. Methotrexate enters the cell through an active transport mechanism of reduced folates. As a result of polyglutamation of methotrexate caused by the folylpolyglutamylate 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 increasing tissues, such as malignant cells, bone marrow, fetal cells, skin epithelium, oral and intestinal mucosa as well as urinary bladder cells. As the proliferation of malignant cells is higher than that of most normal cells, methotrexate can slow down the proliferation of malignant cells without causing, however, 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 precursor synthesis caused by the DNA and RNA.

5.2 Pharmacokinetic properties

The effect of orally administered methotrexate seems to be 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. Saturation of the absorption starts at doses above 30 mg/m2 and absorption at doses exceeding 80 mg/m2 is incomplete.

About half of the absorbed methotrexate binds reversibly to serum protein, but is readily distributed in tissues. The elimination follows a triphasic pattern. Excretion takes place mainly via the kidneys. Approximately 41% of the dose is excreted unchanged in the urine within the first six hours, 90% within 24 hours. A minor part of the dose is excreted in the bile of which there is pronounced enterohepatic circulation.

The half-life is approximaltey 3–10 hours following low dose treatment and 8–15 hours following high dose treatment. If the renal function is impaired, the concentration of methotrexate in serum and in tissues may increase rapidly. Half-life may be prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites).

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. Pharmaceutical particulars
6.1 List of excipients

Anhydrous calcium hydrogen phosphate,

Lactose monohydrate,

Sodium starch glycolate,

Microcrystalline cellulose,

Talc,

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.

Blister: keep the blister in the outer carton in order to protect from light.

HDPE container: store in original container in order to protect from light.

6.5 Nature and contents of container

2.5 mg tablets:

White high density polyethylene container with non CRC high density polyethylene cap with induction wad. Pack size: 25 or 100 tablets

Amber colour Polyvinylchloride (PVC)/Plain Aluminium blister foil. Pack size: 10, 24, 25, 28 30, 50 or 100 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Women who are pregnant, planning to be or breast-feeding should not handle methotrexate.

Parents, care givers and patients should be advised to keep methotrexate out of the reach of children, preferably in a locked cupboard.

Accidental ingestion can be lethal for children.

Anyone handling methotrexate should wash their hands after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling methotrexate.

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

7. Marketing authorisation holder

Cipla (EU) Limited

Dixcart House, Addlestone Road,

Bourne Business Park, Addlestone, Surrey,

KT15 2LE, United Kingdom

8. Marketing authorisation number(s)

PL 36390/0174

9. Date of first authorisation/renewal of the authorisation

23-Jan-15

10. Date of revision of the text

28-Nov-19