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| نشرة الممارس الصحي | نشرة معلومات المريض بالعربية | نشرة معلومات المريض بالانجليزية | صور الدواء | بيانات الدواء |
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Antirheumatic: Active rheumatoid arthritis in adult patients where treatment with disease modifying antirheumatic drugs (DmARDs) is indicated.
Polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA) when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate.
Antipsoriatic: Severe and generalized psoriasis vulgaris, especially plaque-type, in adults which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids.
Cytostatic: Maintenance treatment in acute lymphatic leukaemia.
Important warning about the dosage of Methotrexat “Ebewe” 2.5mg Tablet (methotrexate)
In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis and psoriasis, Methotrexat “Ebewe” 2.5mg Tablet (methotrexate) must only be taken once a week. Dosage errors in the use of Methotrexat “Ebewe” 2.5mg Tablet (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.
Methotrexat “Ebewe” should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy.
The prescriber should specify the day of intake on the prescription.
The prescriber should ensure that patients or their carers will be able to comply with the once weekly regimen.
Dosage: The tablets should be taken 1 hour before or 1.5-2 hours after a meal.
Rheumatoid arthritis and psoriasis: The preparation should only be used by specialists in dermatology, rheumatology and internal medicine.
Psoriasis:
The recommended initial dose is a single dose of 7.5 mg once weekly with escalation of 2.5mg per week.
Rheumatoid arthritis:
Initial dose of 7.5 mg (10mg) weekly given as a single dose, with escalation of 5 mg every month up to the maximum tolerated level not exceeding 25 (30) mg/week; parenteral administration should be considered in the case of inadequate clinical response or intolerance.
The therapeutic effect is usually reached within 6 weeks, with an improvement in the patient’s status after a further 12 weeks or more. If no response is obtained after 6-8 weeks and no toxic symptoms are observed, the dose can be increased gradually as stated above.
If no response is obtained after 8 weeks with the maximum dose, methotrexate should be discontinued. When a response to treatment is obtained, the maintenance dose should be reduced to the lowest possible dose. The optimum treatment duration is at present unknown, but provisional data indicate that the effect obtained initially will persist for at least 2 years if the maintenance dose is continued.
When the treatment is stopped, the symptoms can return over the course of 3-6 weeks.
Dosage in children and adolescents with polyarthritic forms of juvenile idiopathic arthritis
The recommended dose is 10-15 mg/m² body surface area (BSA)/week. In therapy-refractory cases the weekly dosage may be increased up to 20mg/m2 body surface area/week. However, an increased monitoring frequency is indicated if the dose is increased.
Patients with JIA should always be referred to a rheumatology unit specializing in the treatment of children/adolescents.
Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety are available for this population. (see section 4.4)
Cytostatic:
Oral administration of methotrexate at doses of up to 30 mg/m2 is possible, while higher doses should be given parenterally.
Dosage in patients with renal impairment
Methotrexate should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:
Creatinine clearance (ml/min)
> 50 100% of dose
20-50 50% of dose
< 20 Methotrexate must not be used
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.
The prescriber should specify the day of intake on the prescription.
The prescriber should make sure patients understand that Methotrexate 2.5mg Tablet (methotrexate) should only be taken once a week.
Patients should be instructed on the importance of adhering to the once-weekly intakes.
Toxicity
Patients undergoing methotrexate therapy must be closely monitored due to the possibility of severe toxic reactions (which can be fatal) so that signs of possible toxic effects may be detected and evaluated with minimal delay.
Patients must be informed about the possible benefit and the risks (including early signs and symptoms of toxicity) of methotrexate therapy. Furthermore, they are to be informed about the necessity to immediately consult the physician if symptoms of intoxication occur and informed about the subsequently necessary monitoring of the symptoms of intoxication (including laboratory tests).
Withdrawal of methotrexate does not always lead to complete remission of adverse reactions.
Treatment with methotrexate requires that the methotrexate serum level can be determined. Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression.
Methotrexate is excreted only slowly from pathological accumulations of fluid in body cavities (so- called “third space”), such as ascites or pleural effusion, leading to prolonged plasma elimination half- life and unexpected toxicity.
These fluid accumulations are to be removed prior to methotrexate therapy, if possible by puncture.
Gastrointestinal disorders
If ulcerative stomatitis or diarrhoea, haematemesis, black discolouration of the stool or blood in stool occur, therapy is to be interrupted, as otherwise haemorrhagic enteritis and deaths due to intestinal perforation may occur.
Blood and lymphatic system
Methotrexate can suppress haematopoiesis, causing anaemia, aplastic anaemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia.
First signs for these life-threatening complications may be: fever, sore throat, ulcerations of oral mucosa, influenza-like complaints, strong exhaustion, epistaxis and dermatorrhagia.
In the treatment of neoplastic diseases, methotrexate therapy should be continued only if the possible benefit outweighs the risk of severe myelosuppression.
Particularly during long-term therapy in geriatric patients megaloblastic anaemia has been reported. In the condition after treatment with medicinal products with cumulative myelotoxicity as well as
irradiation including the bone marrow, impaired bone marrow reserve is to be heeded. This may result in increased sensitivity of the bone marrow towards methotrexate therapy with enhanced suppression of the haematopoietic system.
During longer-term therapy with methotrexate bone marrow biopsies are to be performed, if needed.
In case of acute lymphatic leukaemia, methotrexate can cause pain in the left upper abdomen (inflammation of the splenic capsule due to destruction of leukaemic cells).
Liver function
On account of its potential hepatotoxic effect it is recommended not to consume any additional hepatotoxic medicinal products or medicinal products considered to be hepatotoxic and to refrain from alcohol resp. to minimise alcohol consumption during therapy with methotrexate.
Methotrexate may provoke a potential risk of acute hepatitis and chronic potentially fatal hepatotoxicity (fibrosis and cirrhosis), however typically occurring only after prolonged use. Acute increases of liver enzymes are frequently observed. These are usually transient and asymptomatic and are no signs of subsequent liver diseases.
Methotrexate caused reactivation of hepatitis B infections and exacerbation of hepatitis C infection, in some cases fatal. Some cases of reactivation of hepatitis B occurred after discontinuation
of methotrexate. To assess pre-existing liver disease in patients with a history of hepatitis B or C infection clinical and laboratory tests should be performed. Based on these tests, treatment with methotrexate might be not appropriate for some patients.
Furthermore, in the presence of an inactive, chronic infection such as herpes zoster or tuberculosis special caution is required on account of a possible activation.
In general special caution is required in patients with existing insulin-dependent diabetes mellitus as isolated cases of liver cirrhosis without intermittent increase of transaminases occurred under methotrexate therapy.
Renal function
In patients with renal function impairment, methotrexate therapy should be performed only with increased caution and low dose because of delayed methotrexate elimination in these patients (see section 4.2).
Therapy with methotrexate may cause deterioration of renal function with an increase in certain laboratory values (creatinine, urea, serum uric acid) that may result in acute renal failure with oliguria/anuria. This is probably attributable to precipitation of methotrexate and its metabolites in the renal tubuli.
Conditions leading to dehydration such as emesis, diarrhoea, stomatitis, can increase the toxicity of methotrexate due to elevated agent levels. In these cases, supportive therapy should be initiated and use of methotrexate should be interrupted until the symptoms cease.
Nervous system
Chronic leukoencephalopathy occurred in patients receiving repeated methotrexate high-dose therapy together with calcium folinate rescue without prior cranial irradiation. There are reports of leukoencephalopathy in patients who received oral methotrexate.
Pulmonary function
Special caution is required in patients with impaired pulmonary function.
Pulmonary complications, pleural effusion, alveolitis or pneumonitis with symptoms such as dry cough, fever, malaise, cough, chest pain, dyspnoea, hypoxaemia, and infiltrates in the chest x-ray or unspecific pneumonia occurring during methotrexate therapy may be signs of a potentially dangerous injury with possible fatal outcome. Lung biopsies provided different findings (e.g. interstitial oedema, mononuclear infiltrates or non-caseating granulomas). On suspicion of these complications, treatment with methotrexate must be discontinued immediately and a thorough investigation excluding infections and tumours is required. Methotrexate induced lung disease may occur any time during acute therapy, were not always fully reversible and have been reported at 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.
Skin and subcutaneous tissue
Serious, sometimes fatal, skin reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome), were reported after single or continuous administration of methotrexate.
Psoriatic lesions can exacerbate due to UV radiation during concomitant treatment with methotrexate. Dermatitis and sunburn caused by radiation can recur during use of methotrexate (so-called “recall” reactions).
Immune system
Potentially fatal opportunistic infections, including pneumocystis-jirovecii pneumonia, may occur during treatment with methotrexate. In patients presenting with pulmonary symptoms pneumocystis- jirovecii pneumonia must be taken into consideration.
Methotrexate may, due to its possible effect on the immune system, impair the response to
vaccinations and interfere with results of immunological tests (to assess the immune reaction). Vaccinations during methotrexate therapy can be ineffective.
Due to the increased risk of infection no live vaccines should be performed during therapy with methotrexate.
Neoplasms
In patients with rapidly growing tumours, methotrexate, as other cytostatic medicinal products, can induce a tumour lysis syndrome. Appropriate supportive and pharmacological measures can prevent or reduce these complications.
The occurrence of malignant lymphomas has uncommonly been reported during use of low-dosed methotrexate; they subsided in some cases after therapy with methotrexate was withdrawn. If lymphomas occur, methotrexate therapy should therefore be stopped first and only if the lymphoma does not subside, appropriate therapy should be initiated. In a more recent study an increased incidence for the occurrence of lymphomas during methotrexate treatment could not be detected.
Musculoskeletal, connective tissue and bone disorders
Radiotherapy during use of methotrexate can increase the risk of soft tissue or bone necrosis.
Folic acid supplementation
Folate deficiency states may increase toxicity of methotrexate (see section 4.5).
The use of folic acid or folinic acid may reduce the toxicity of methotrexate (gastrointestinal symptoms, stomatitis, alopecia and increase in liver enzymes).
Before taking folic acid preparations, it is advisable to check the vitamin B12 levels, as folate intake can mask a vitamin B12 deficiency condition, especially in adults over the age of 50 years.
Recommended follow-up check-ups and safety measures
The following investigations should be performed prior to therapy:
- complete blood count with differential blood count,
- liver enzymes (ALAT [GPT], ASAT [GOT], AP),
- bilirubin,
- serum albumin,
- renal retention test (if necessary with creatinine clearance),
- hepatitis serology (A, B, C),
- if necessary exclusion of tuberculosis as well as thoracic X-ray.
Pulmonary function tests may be beneficial if a pulmonary disease (e.g., interstitial pneumonia) is suspected or if relevant reference values exist from the first examination.
Regular monitoring of the methotrexate serum level is necessary, depending on the dose or the treatment protocol used, particularly during and after therapy with methotrexate at high dose (see also section 4.9). By adjusting the dose of methotrexate and implementing appropriate rescue measures, the toxicity and potential mortality of methotrexate treatment can be significantly reduced.
Patients suffering from pleural effusions, ascites, occlusion in the gastrointestinal tract, preceding cisplatin therapy, dehydration, reduced urinary pH or impaired renal function are particularly at risk of developing elevated methotrexate levels or methotrexate levels only declining with delay; they must be strictly monitored. Some patients may also have delayed methotrexate excretion even without the named discernible reasons. It is important to identify these patients within 48 hours after therapy, as otherwise methotrexate toxicity may be irreversible.
During methotrexate therapy the blood count, including thrombocyte and leukocyte count must be
monitored continuously (daily up to once weekly).
Prior to the start of a combination therapy including methotrexate at high dose, the leukocyte and thrombocyte count should be above the minimum values stated in the relevant treatment protocol (leukocytes 1,000 to 1,500/µl, thrombocytes 50,000 to 100,000/µl).
The nadir of circulating leukocytes, neutrophils and thrombocytes usually occurs between 5 and 13 days after an iv methotrexate administration (with recovery between 14 to 28 days). Leukocytes and neutrophils may occasionally show two depressions, the first occurring in 4-7 days and a second nadir after 12-21 days, followed by recovery.
Hepatic and renal function tests as well as urinalysis should be carried out at regular intervals.
Transient increases in transaminases to the 2-3-fold are observed in 13-20% of patients treated with methotrexate. This is usually no reason to change the treatment scheme. However, persistent abnormality of liver enzymes and/or decrease in serum albumin may be a sign of severe hepatotoxicity. In case of persistently increased liver enzymes, dose reduction or interruption of therapy, respectively is to be considered. In patients with long-term existing hepatic dysfunctions, methotrexate should in any case be discontinued. Enzyme diagnostics does not allow for any reliable prediction of the development of a morphologically detectable hepatotoxicity, i.e. even in case of normal transaminases, an only histologically identifiable hepatic fibrosis or, more rarely, cirrhosis may be present.
In rheumatological indications, there is no evidence to support use of liver biopsies in monitoring hepatotoxicity. For psoriasis patients the need of a liver biopsy prior to and during therapy is controversial. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. This assessment should differentiate between patients without any risk factors and patients with risk factors, e.g. 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 or cumulative doses of 1.5 g or more.
Monitoring of creatinine, urea and electrolytes is recommended on days 2 and 3, in order to diagnose an imminent excretion disorder of methotrexate in an early stage.
If there is evidence of impaired renal function (e.g. profound side effects of preceding methotrexate therapy or urinary obstruction), creatinine clearance is to be determined.
If creatinine values are increased, the dose should be reduced; for serum creatinine values >2 mg/dl methotrexate therapy should not be initiated. In case of borderline renal function (e.g. in higher age) monitoring should be close. This particularly applies when additional medicinal products are given that can impair methotrexate excretion, cause nephrotoxicity (e.g. non-steroidal antirheumatics) or lead to haematopoietic disorders.
Oral cavity and pharynx should be inspected daily for mucosal alterations.
Particularly strict monitoring of the patient is required in preceding intensive radiotherapy, reduced general status as well as juvenile or high age.
More frequent check-ups may be necessary when initiating treatment, changing the dose or during episodes of increased risk of elevated methotrexate levels (e.g. dehydration, impaired renal function, additional or increased administration of concomitant medicinal products, such as non-steroidal antirheumatics).
Fertility Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after the discontinuation of treatment, 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 malformations in humans. Therefore, the possible effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing age (see section 4.6). In non-oncologic indications, the absence of pregnancy must be confirmed before Methotrexate 2.5mg Tablet is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after.
For contraception advice for men see section 4.6.
Use in children and adolescents
Special caution should be taken in the use of methotrexate for the treatment of children. Treatment should be guided by the treatment protocols developed specifically for children.
Use in elderly patients
Special caution is also required in patients of higher age. The patients should be examined at short intervals for early signs of toxicity.
Clinical pharmacology of methotrexate in higher age has not yet been completely investigated. The dose of methotrexate should be adjusted to hepatic and renal functions reduced on account of higher age. Partially modified treatment protocols, e.g. for the treatment of ALL, have been developed for patients of higher age (from 55 years on).
Methotrexate 2.5mg Tablet tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The absence of pregnancy should be confirmed before Methotrexate 2.mg tablet is administered.
L-asparaginase antagonises the effects of methotrexate during concomitant administration with methotrexate.
Colestyramine can increase the non-renal elimination of methotrexate due to interruption of the enterohepatic circulation.
Concomitant administration of erythrocyte concentrates and methotrexate requires special monitoring of the patients as increased toxicity may occur due to prolonged high serum concentrations of methotrexate.
The concurrent use of medicinal products causing folate deficiency (e.g., sulphonamides, trimethoprim-sulfamethoxazole) may lead to increased toxicity of methotrexate. Special caution is therefore also required in already existing folic acid deficiency.
On the other hand, concomitant administration of folic acid containing medicinal products as well as vitamin preparations containing folic acid or their derivatives can impair the efficacy of methotrexate.
Hepatotoxicity of methotrexate can be increased during regular consumption of alcohol or administration of other hepatotoxic medicinal products, e.g. azathioprine, leflunomide, retinoids, sulfasalazine. Patients who take hepatotoxic medicinal products in addition should be closely monitored. Alcohol consumption should be avoided during methotrexate treatment.
In isolated cases, corticosteroids led to disseminated herpes zoster in patients with herpes zoster or post-herpetic neuralgia and concomitant use of methotrexate.
The combined use of methotrexate with leflunomide may increase the risk of pancytopenia.
Concomitant use of mercaptopurine and methotrexate can increase the plasma level of mercaptopurine, so that dose adjustment may be necessary during concomitant use.
In an animal trial, non-steroidal anti-inflammatory drugs (NSAIDs), including salicylic acid led to a reduction in tubular secretion of methotrexate and thus to an increase in its toxicity due to elevated methotrexate levels. Therefore, NSAIDs and low-dose methotrexate should be used concurrently only with caution.
However, in clinical studies, where NSAIDs and salicylic acid were given as concomitant medication to patients with rheumatoid arthritis, no increase of adverse reactions was observed. Treatment of rheumatoid arthritis with such drugs can be continued during low-dose methotrexate therapy but only under close medical supervision.
Serious side effects, including deaths, including unexpectedly strong bone marrow suppression, aplastic anaemia and gastrointestinal toxicity, have been reported with concomitant use of NSAIDs and, particularly high dose methotrexate.
In the presence of risk factors, e.g. borderline renal function, the concurrent use of NSAIDs and methotrexate is not recommended.
Concomitant use of methotrexate and basic therapeutics (e.g., gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine) has not been studied and an increase in the toxic effects of methotrexate can not be ruled out.
The combination of methotrexate and sulfasalazine can enhance the effect of methotrexate, as sulfasalazine causes inhibition of folic acid synthesis. This can result in an increased risk of adverse reactions, although in several studies this was only observed in individual patients.
Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad spectrum antibiotics can reduce the intestinal absorption of methotrexate or influence enterohepatic circulation by inhibiting intestinal flora and bacteria-related methotrexate metabolism.
Penicillins and sulfonamides may reduce the renal clearance of methotrexate in the isolated case, so that increased serum concentrations of methotrexate may occur with concurrent haematological and gastrointestinal toxicity.
The renal tubular secretion is reduced by ciprofloxacin; the use of methotrexate with this medicinal product should be carefully monitored.
Pyrimethamine or cotrimoxazole used in combination with methotrexate may cause pancytopenia, probably by additive inhibition of dihydrofolic acid reductase due to these substances and methotrexate (interactions between sulphonamides and methotrexate see above).
Concomitant administration of proton pump inhibitors (omeprazole, pantoprazole, lansoprazole) may lead to delayed or inhibited renal elimination of methotrexate and thus to increased methotrexate plasma levels with clinical signs and symptoms of methotrexate toxicity. Particularly, in patients with renal impairment caution is required.
Methotrexate can reduce the theophylline clearance. Therefore, theophylline levels should be monitored when concomitantly used with methotrexate.
The following medicinal products can increase bioavailability of methotrexate (indirect dose increase) and raise its toxicity due to displacement of methotrexate from the plasma protein binding: amidopyrine derivatives, para-aminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulphonamides, tetracyclines, tranquillizers, sulfonylureas, penicillins, pristinamycin and chloramphenicol. Concomitant use of methotrexate should therefore be carefully monitored.
The following medicinal products can cause a reduction in tubular secretion and consequently increased toxicity of methotrexate, particularly in the low dose range: para-aminohippuric acid, non- steroidal anti-inflammatory drugs, probenecid, salicylates, sulphonamides and other weak organic acids. Concomitant use of methotrexate should therefore be monitored carefully.
During (pre-)treatment with medicinal products presenting possible adverse reactions on the bone marrow (e.g. amidopyrine derivatives, chloramphenicol, phenytoin, pyrimethamine, sulphonamides, trimethoprim-sulfamethoxazole, cytostatics), the possibility of profound haematopoietic disorders due to therapy with methotrexate is to be heeded.
Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.
Vaccines containing live vaccines should not be used during therapy with methotrexate (see section 4.4).
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 medicinal products.
The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and in case of intrathecal administration increased severe, unpredictable neurotoxicity. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided.
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, in particular at doses commonly used in oncologic indications.
When methotrexate was discontinued prior to conception, normal pregnancies have been reported.
When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate, the patient should be informed of the potential risk to the foetus.
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.
Breastfeeding:
As methotrexate passes into breast milk and may cause toxicity in breast-fed infants, breast-feeding is contraindicated during treatment (see section 4.3). If use during lactation is considered, breast-feeding has to be stopped prior to treatment is started.
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. In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate can be genotoxic at higher doses (see section 4.4).
As adverse reactions of the central-nervous system such as fatigue and dizziness may occur during use of methotrexate, the ability to drive and/or operating machinery can be impaired in isolated cases. This applies to an increased extent in conjunction with alcohol.
Occurrence and severity of undesirable effects depend on dose, method and duration of methotrexate administration. However, as severe adverse reactions may occur even at lower doses at any time, it is indispensable that the physician monitors patients regularly at short intervals.
Most undesirable effects are reversible if recognised early.
However, some of the serious adverse reactions listed below may result in sudden death in very rare cases.
If adverse reactions occur, the dose should be reduced or the therapy be interrupted depending on severity and intensity, and appropriate measures should be taken (see section 4.9). If methotrexate therapy is resumed, it should be continued with caution under thorough assessment of the necessity of therapy and with increased alertness for the possible reoccurrence of toxicity.
Myelosuppression and mucositis are usually the dose-limiting toxic effects. Their severity depends on the dose, the mode and duration of use of methotrexate. Mucositis appears approx. 3-7 days after the use of methotrexate, leukopenia and thrombocytopenia occur 5-13 days after methotrexate use.
Myelosuppression and mucositis are generally reversible within 14 days in patients with undisturbed elimination mechanisms.
The adverse reactions most commonly reported are thrombocytopenia, leukopenia, headache, vertigo, cough, loss of appetite, diarrhoea, abdominal pain, nausea, vomiting, ulcerative stomatitis (particularly within the first 24-48 hours after administration of methotrexate), increase in hepatic enzymes and bilirubin, alopecia, lowered creatinine clearance, fatigue and malaise.
Ulcerative stomatitis is usually the first sign of toxicity.
Frequencies in this table are defined using the following convention: 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).
Further details are given following this table.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness
| Very common | Common | Uncommon | Rare | Very rare | Unknown |
Infections and infestation s |
| Herpes zoster | Opportunisti c infections which may be lethal | Sepsis, (including lethal sepsis) | Herpes simplex hepatitis, cryptococcos is, histoplasmos is, cytomegalovi rus infections including pneumonia, disseminated herpes simplex, nocardiosis, pneumocysti s-jirovecii pneumonia* | Pneumonia, reactivation of hepatitis B infection, exacerbation of hepatitis C infection |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| Malignant lymphoma* |
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Blood and lymphatic | Thromb- ocytopenia, | Anaemia, pancyto- |
| Megalo- blastic | Aplastic anaemia, |
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| Very common | Common | Uncommon | Rare | Very rare | Unknown |
system | leukopenia | penia, |
| anaemia | eosinophilia, |
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disorders * |
| myelosuppre |
| neutropenia | ||
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| lymphadenop | ||
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Immune |
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system | reactions to | - | ||||
disorders* | anaphylactic | globulinaemi | ||||
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Metabolis |
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Nervous | Headache, | Drowsiness, | Hemiparesis, | Paresis, | Myasthenia | Neurotoxicity, |
system | vertigo | paraesthesia | confusion, | speech | and pain, in | arachnoiditis, |
disorders |
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| disorders | the | paraplegia, |
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| including | extremities, | stupor, ataxia, |
|
|
|
| dysarthria | dysgeusia | dementia, |
|
|
|
| and aphasia, | (metallic | increase in the |
|
|
|
| leukoence- | taste), acute | pressure of |
|
|
|
| phalopathy | aseptic | cerebrospinal |
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| meningitis, | fluid |
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| meningism |
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| (paralysis, |
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| vomiting), |
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| cranial nerve |
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|
|
| syndrome |
|
Eye |
| Conjuncti- |
| Visual | Periorbital |
|
disorders | vitis | impairment | oedema, | |||
|
| (partly | blepharitis, | |||
|
| severe), | epiphora, | |||
|
| severe | photophobia, | |||
|
| retinal vein | transient |
| Very common | Common | Uncommon | Rare | Very rare | Unknown |
|
|
|
| thrombosis | blindness, loss of vision |
|
Cardiac disorders |
|
|
|
| Pericarditis, pericardial effusion, pericardial tamponade |
|
Vascular |
|
| Vasculitis, | Hypotensio |
|
|
disorders | allergic | n, thromb- | ||||
| vasculitis | oembolic | ||||
|
| events | ||||
|
| (including | ||||
|
| arterial | ||||
|
| thrombosis, | ||||
|
| cerebral | ||||
|
| thrombosis, | ||||
|
| thrombophl | ||||
|
| ebitis, deep | ||||
|
| vein | ||||
|
| thrombosis) | ||||
|
| , | ||||
Respirator | Cough | Pulmonary | Pulmonary | Pharyngitis, | Chronic | Pulmonary |
y, thoracic |
| complication | fibrosis, | respiratory | interstitial | alveolar |
and |
| s due to | pleural | arrest, | pulmonary | haemorrhage** |
mediastina |
| interstitial | effusion | pulmonary | disease, | , chest pain, |
l |
| alveolitis/pn |
| embolism | asthma | hypoxia |
disorders* |
| eumonitis |
|
| bronchiale- |
|
|
| and related |
|
| like reactions |
|
|
| deaths |
|
| with cough, |
|
|
| (regardless |
|
| dyspnoea and |
|
|
| of dose and |
|
| pathological |
|
|
| duration of |
|
| findings in |
|
|
| treatment |
|
| pulmonary |
|
|
| with |
|
| function test |
|
|
| methotrexate |
|
|
|
|
|
| ). |
|
|
|
|
Gastrointe | Loss of |
| Gastro- | Enteritis, | Haematemesi | Non-infectious |
stinal | appetite, | intestinal | gingivitis, | s | peritonitis, | |
disorders* | diarrhoea | ulcers and | melaena, |
| intestinal | |
| (particularly | haemorrhage |
|
| perforation, | |
| within the | s, |
|
| glossitis | |
| first 24-48 | pancreatitis |
|
|
| |
| hours after |
|
|
|
| |
| administrati |
|
|
|
| |
| on of |
|
|
|
| |
| methotrexat |
|
|
|
| |
| e), |
|
|
|
| |
| abdominal |
|
|
|
| |
| pain, |
|
|
|
| |
| nausea, |
|
|
|
|
| Very common | Common | Uncommon | Rare | Very rare | Unknown |
| vomiting, ulcerative stomatitis (particularly within the first 24-48 hours after administrati on of methotrexat e). |
|
|
|
|
|
Hepato- biliary disorders* | Increase in hepatic enzymes (ALAT [GPT], ASAT [GOT], alkaline phosphatase and bilirubin). |
| Hepatotoxici ty, hepatosteatos is, chronic hepatic fibrosis and cirrhosis, drop of serum albumin. | Acute hepatitis | Acute hepatic necrosis, acute hepatic degeneration, hepatic failure |
|
Skin and subcutaneo us tissue disorders* | Alopecia | Exanthema, erythema, pruritus, photosensiti vity, skin ulceration | Stevens- Johnson syndrome*, toxic epidermal necrolysis (Lyell’s syndrome)*, as severe toxic phenomena; herpetiform skin eruptions, urticaria, increased pigmentation of the skin, nodulosis,. impaired wound healing | Acne, petechiae, ecchymosis, erythema multiforme, erythematou s rashes, increased pigmentatio n of the nails, oncholysis | Furunculosis, telangiectasia , acute paronychia | Drug reaction with eosinophilia and systemic symptoms (DRESS), dermatitis |
Musculosk eletal and connective tissue disorders |
|
| Arthralgia, myalgia, osteoporosis | Stress fracture |
| Osteonecrosis of jaw (secondary to lymphoprolifer ative disorders) |
| Very common | Common | Uncommon | Rare | Very rare | Unknown |
Renal and | Decreased |
| Nephropathy | Hyperuricae | Haematuria, |
|
urinary | creatinine | , renal | mia, | proteinuria | ||
disorders* | clearance | failure, | increased |
| ||
|
| cystitis with | urea and |
| ||
|
| ulceration | creatinine |
| ||
|
| (possibly | serum |
| ||
|
| with | concentratio |
| ||
|
| haematuria), | n,, |
| ||
|
| voiding | azotaemia |
| ||
|
| disorder, |
|
| ||
|
| dysuria, |
|
| ||
|
| oliguria, |
|
| ||
|
| anuria |
|
| ||
Pregnancy, |
|
| Foetal | Abortion | Foetal death |
|
puerperiu | abnormalitie |
|
| |||
m and | s |
|
| |||
perinatal |
|
|
| |||
conditions |
|
|
| |||
Reproducti |
|
| Vaginal | Transient | Impaired | Urogenital |
ve system | inflammation | oligospermi | ovogenesis/s | dysfunction | ||
and breast | and | a, transient | permatogene |
| ||
disorders | ulceration | menstrual | sis*, |
| ||
|
| disorders | infertility*, |
| ||
|
|
| cycle |
| ||
|
|
| disturbances, |
| ||
|
|
| loss of libido, |
| ||
|
|
| impotence, |
| ||
|
|
| vaginal |
| ||
|
|
| discharge, |
| ||
|
|
| gynaecomast |
| ||
|
|
| ia |
| ||
General | Fatigue, |
| Pyrexia |
|
| Chills |
disorders | malaise |
|
| |||
and |
|
|
| |||
administra |
|
|
| |||
tion site |
|
|
| |||
conditions |
|
|
|
*For information regarding serious side effects see section 4.4
**(has been reported for methotrexate used in rheumatologic and related indications)
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.
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.
E.g. leukopenia, thrombocytopenia, anaemia, pancytopenia, neutropenia, myelosuppression, mucositis, stomatitis, ulcers in the mouth, nausea, vomiting as well as gastrointestinal ulceration and haemorrhages occurred. In some cases, there were no signs of intoxication.
There are also reports on deaths as a result of an overdose. In these cases sepsis, septic shock, renal failure and aplastic anaemia have also been reported.
Therapeutic measures in case of overdose
Calcium folinate is available as specific antidote to prevent and treat toxic adverse reactions of methotrexate.
In the event of a decline of leukocytes following low methotrexate dose, e.g. 6-12 mg calcium folinate may be injected i.v. or i.m. immediately, followed by several times (at least 4 times) the same dose at 3-6-hour intervals.
The efficacy of calcium folinate decreases with increasing interval between methotrexate administration and use of calcium folinate. To determine the optimal dose and duration of calcium folinate administration, monitoring of methotrexate serum levels is necessary.
In the event of a massive overdose, hydration and alkalisation of the urine may be necessary in order to avoid precipitation of methotrexate and/or its metabolites in renal tubuli.
If the intoxication is caused by considerably delayed elimination (methotrexate serum levels) e.g. as a result of acute renal insufficiency, haemodialysis and/or haemoperfusion may be taken into consideration.
An effective methotrexate clearance was achieved through a haemodialysis with a high-flux dialyser. Neither standard haemodialysis nor peritoneal dialysis led to an improved elimination of methotrexate.
In patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriasis arthritis or psoriasis vulgaris, administration of folic or folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms, inflammation of oral mucosa, hair loss and increase of liver enzymes), see section 4.5. Prior to using folic acid products, monitoring of vitamin B12 levels is recommended, since folic acid may mask an existing vitamin B12 deficiency, particularly in adults over 50 years of age.
Pharmacotherapeutic group:
Other immunosuppressants, ATC-code: L04AX03 Antimetabolites, folic acid and analogues, ATC-code: L01BA01
Methotrexate is a folic acid antagonist which belongs to the class of cytotoxic agents known as antimetabolites. It acts by the competitive inhibition of the enzyme dihydrofolate reductase and thus inhibits DNA synthesis. It has not yet been clarified, as to whether the efficacy of methotrexate, in the management of psoriasis, psoriasis arthritis and chronic polyarthritis, is due to an anti-inflammatory or immunosuppressive effect and to which extent a methotrexate-induced increase in extracellular adenosine concentration at inflamed sites contributes to these effects.
After oral application, methotrexate is absorbed from the gastrointestinal tract. When administered in low doses (7.5mg/m2 to 80mg/m2 body surface area), methotrexate has a mean bioavailability of approximately 70%, although considerable inter- and intra-subject variations are possible (25-100%). Plasma peak concentrations are attained within 1-2 hours. Subcutaneous, intravenous and intramuscular administration demonstrated similar bioavailability. Approximately 50% of methotrexate is bound to serum proteins. Upon being distributed into body tissues, high concentrations particularly in liver, kidneys and spleen in form of polyglutamates can be found, which can be retained for weeks or months. When administered in small doses, methotrexate passes into the liquor in minimal amounts; under high doses (300mg/kg body weight), concentrations between 4 and 7 μg/ml have been measured in the liquor. Average terminal half-life is 6-7 hours and demonstrates considerable variation (3-17 hours). Half-life may be prolonged to 4 times the normal length in patients with third spaces (pleural effusion, ascites). Approximately 10% of the administered methotrexate is metabolised intrahepatically. The major metabolite is 7-hydroxymethotrexate.
Excretion takes place, mainly in unchanged form, primarily renal via glomerular filtration and active secretion in the proximal tubulus. Approx. 5-20% of methotrexate and 1-5% of 7- hydroxymethotrexate are eliminated via the bile. Pronounced enterohepatic blood flow exists.
In case of renal insufficiency, elimination is delayed significantly. Impaired elimination in presence of hepatic insufficiency is not known.
Methotrexate passes the placental barrier in rats and monkeys.
Chronic toxicity
Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity.
Mutagenic and carcinogenic potential
Long-term studies in rats, mice and hamsters did not show any evidence of a tumorigenic potential of methotrexate. Methotrexate induces gene and chromosome mutations both in vitro and in vivo. A mutagenic effect is suspected in humans.
Reproductive toxicology
Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys, no malformations comparable to humans occurred.
Lactose monohydrate
Maize starch
Microcrystalline cellulose
Magnesium stearate
Colloidal anhydrous silica
Not applicable.
Store below 25◦C
Tablet container (white polypropylene) with white lid (polyethylene).
2.5 mg tablets: 20, 25, 30, 50 and 100 tablets
PVC/PVDC-Alu blister
2.5 mg tablets: 50 tablets
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
