Section 4.2

Important warning information about dosage has been reworded.

The planned weekly dose may be administered in three divided doses over 24 hours, changed from 36 hours.

Addition of information about patients with renal impairment and third distribution space (pleural effusions, ascites):

“Patients with 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)      Dose

≥ 60                                              100%

30-59                                            50%

< 30                                              Methotrexate must not be used.

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.”

Section 4.3

“Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease” has been added as a contra-indication.

Section 4.4

Information has been added about Methotrexate-induced lung diseases, such as pneumonitis and pulmonary alveolar haemorrhage.

Detailed information has been deleted on who is at risk of hepatotoxity and when liver biopsy is recommended and replaced with the following information: 

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

“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.”

Information about renal function has been updated: 

“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.”

Further information on diarrhoea and ulcerative stomatitis has been added:

“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.”

The following information has also been added:

“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.

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.

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.”

Section 4.5

Additional medicinal products have been listed that decrease the binding of methotrexate to serum albumin:

“phenylbutazone, barbiturates, tranquilisers, oral contraceptives, amidopyrine derivatives, p-aminobenzoic acid, thiazide diuretics, oral hypoglycaemics and doxorubicin”

The information about the interaction with antibiotics has been updated:

“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.”

Added: Coadministration of hematotoxic should also be avoided with methotrexate. “Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the probability of severe haematoxic effects of methotrexate.”

Information clarified:

“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. 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.”

Information added:

“In combination with pantoprazole, inhibited renal elimination of the 7-hydroxymethotrexate metabolite, with myalgia and shivering, was reported in one case.

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.

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.

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).

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.”

Section 4.6 has been completely updated.

Section 4.8:

The following information has been added:

“Methotrexate therapy should only be resumed [after adverse reactions occur] 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”

The following adverse reactions have been added:

Very common: Dyspepsia, abdominal pain, abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and bilirubin)

Common: Drowsiness, oral ulcers, exanthema

Uncommon: Agranulocytosis, hematopoietic disorders, vertigo, pneumonita⁴, pulmonary fibrosis, decrease in serum albumin, fatty degeneration of the liver, herpetiform eruptions of the skin, increased skin pigmentation, inflammation and ulceration of the urinary bladder, disturbed micturition, vaginal inflammation, chills

Rare: Megaloblastic anemia, mood alterations, paresis, pericardial tamponade, respiratory paralysis, melaena, onycholysis, increased nail pigment changes, petechiae Allergic vasculitis, radiation dermatitis and sunburn may be “recalled”, stress fracture, oliguria, anuria, electrolyte disturbances, azotaemia, fever, wound-healing impairment, asthenia

Not known: Reactivation of inactive chronic infection, anaphylactic shock, allergic reactions, encephalopathy/leuko-encephalopathy, impaired vision, retinopathy, interstitial alveolitis⁴, bronchial asthma, epistaxis, pulmonary alveolar haemorrhage, toxic megacolon, pancreatitis, osteo-necrosis of jaw (secondary to lympho-proliferative disorders), proteinuria

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

Section 5.2

Added: “Half-life may be prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites).”

Section 6.3

Shelf life for 2.5mg tablets in blister has been increased from 2 to 3 years

Section 6.6

Wording added:

“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.”