Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Therakind (Europe) Limited, Paramount Court, Corrig Road, Sandyford Business Park, Dublin 18, D18 R9C7, Ιreland
Additionally for non-oncological indications:
The oral solution contains 2 mg of methotrexate in each ml of solution; the scaling of the dosing syringe is in ml and not mg; care should be taken that the correct dosing volume is prescribed. Patients with rheumatological or dermatological diseases must be informed unequivocally that treatment is to be taken just once a week and not daily. Incorrect use of methotrexate can result in severe and even fatal adverse reactions. Medical staff and patients must be clearly instructed.
The prescriber should specify the day of intake on the prescription. The prescriber should make sure patients understand that Jylamvo (methotrexate) should only be taken once a week.
Patients should be instructed on the importance of adhering to the once-weekly intakes.
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.
Therefore, methotrexate should only be administered by, or under the supervision of, doctors whose knowledge and experience includes treatment with antimetabolites.
Especially strict monitoring of the patient is indicated following prior radiotherapy (especially of the pelvis), functional impairment of the haematopoietic system (e.g., following prior radio- or chemotherapy), impaired general condition as well as advanced age and in very young children. 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 (10 ml)/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 section 4.2).
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.
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.
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 Jylamvo 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.
Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest X-ray and renal function tests. If clinically indicated, tuberculosis and hepatitis B and C should be excluded.
The tests below must be conducted weekly in the first two weeks, then every two weeks for a month; thereafter, depending on the leucocyte count and the stability of the patient, at least once a month during the next six months and then at least every three months.
An increased monitoring frequency should be considered when the dose is increased. In particular, elderly patients should be monitored at short intervals for early signs of toxicity (see section 4.2).
Testing of serum liver enzymes Transient increases in transaminases to twice or three times normal occur in 13-20% of patients. Persistent abnormalities of liver enzymes and/or a decrease in serum albumin can indicate severe hepatotoxicity. 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 function tests or determinations of propeptide of type III collagen are appropriate for detecting hepatotoxicity. This evaluation 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 a hereditary liver disease, diabetes mellitus, obesity and history of significant exposure to hepatotoxic medicinal product or chemicals, as well as prolonged methotrexate treatment or a cumulative total dose of 1.5 g or more.
If liver enzymes are constantly increased, a dose reduction or treatment discontinuation should be considered.
Due to its potentially toxic effects on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless urgently necessary and the consumption of alcohol should be avoided or reduced (see section 4.5). Closer monitoring of liver enzymes should be undertaken in patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). This should also be considered during simultaneous administration of haematotoxic medicinal products.
Increased caution is required in patients with insulin-dependent diabetes mellitus as hepatic cirrhosis has developed in individual cases without any elevation of transaminases during methotrexate treatment.
Treatment with moderately high and high doses of methotrexate should not be initiated at urinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.
In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.
Methotrexate should be discontinued in patients with pulmonary symptoms and an immediate examination (including chest X-ray) should be performed 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.
Pulmonary symptoms require a rapid diagnosis and discontinuation of methotrexate therapy.
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 (3.75 ml)/week).
Opportunistic infections can occur during treatment with methotrexate, including Pneumocystis jiroveci pneumonia, which can also have a fatal outcome. If a patient develops pulmonary symptoms, the possibility of Pneumocystis jiroveci pneumonia should be considered.
Particular caution is required in patients with impaired pulmonary function.
Particular caution is also required in the presence of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) as it is possible that activation of these infections may occur.
As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.
If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.
If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate. (See renal function monitoring)
Due to its effect on the immune system, methotrexate may impair the response to vaccinations and affect the results of immunological tests. Concurrent vaccination using live vaccines should not be given.
Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. If the lymphomas fail to regress spontaneously, cytotoxic treatment must be initiated.
Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment (see section 4.2).
Conditions that cause dehydration such as vomiting, diarrhoea or stomatitis can increase toxicity as a result of raised active substance levels. In this case, treatment with methotrexate must be discontinued until the symptoms have disappeared.
It is important to determine any increase in active substance levels within 48 hours of therapy, otherwise irreversible methotrexate toxicity may occur.
Diarrhoea and ulcerative stomatitis may be signs of toxic effects and require the discontinuation of treatment, 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.
If acute methotrexate toxicity occurs, patients may require treatment with 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.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate (see sections 4.2 and 4.5).
Radiation-induced dermatitis and sunburn can reappear during methotrexate therapy (recall reactions). Psoriatic lesions can worsen during UV radiation and co-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.
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.
This medicinal product contains sodium methyl parahydroxybenzoate (E219) and ethyl parahydroxybenzoate (E214). It may cause allergic reactions (possibly delayed).
The risk of an interaction between NSAIDs and methotrexate should be considered in patients with a low methotrexate dose, particularly in the case of impaired kidney function. If combined treatment is required, the blood count and renal function should be monitored. Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours, since in this case methotrexate plasma levels can rise and toxicity be increased as a result. Animal studies showed that the administration of NSAIDs including salicylic acid resulted in reduced tubular methotrexate secretion and accordingly potentiated its toxic effects. However, in clinical trials in which NSAIDs and salicylic acid were administered adjuvantly to patients with rheumatoid arthritis, no increase in adverse reactions was observed. Treatment of rheumatoid arthritis with such medicinal products can be continued during therapy with low-dose methotrexate, but only under close medical supervision.
Patients taking potentially hepatotoxic medicinal products during treatment with methotrexate (e.g. leflunomide, azathioprine, sulfasalazine and retinoids) should be monitored closely for increased hepatotoxicity. The consumption of alcohol should be avoided during treatment with methotrexate (see section 4.4). Regular alcohol consumption and administration of additional hepatotoxic medicinal products increase the likelihood of hepatotoxic adverse reactions to methotrexate. Administration of additional haematotoxic medicinal products (e.g. metamizole) increases the likelihood of severe haematotoxic adverse reactions to methotrexate.
Pharmacokinetic interactions between methotrexate, anticonvulsants (reduced serum methotrexate levels) and 5-fluoruracil (increased half-life of 5-fluoruracil) must be borne in mind.
Salicylates, phenylbutazone, diphenylhydantoin (= phenytoin), barbiturates, tranquillisers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulphonamides, thiazide diuretics, oral hypoglycaemics, doxorubicin and p-aminobenzoic acid displace methotrexate from serum albumin binding and thus increase bioavailability and hence toxicity (indirect dose increase).
Probenecid and weak organic acids can also reduce the tubular secretion of methotrexate and thus likewise cause an indirect increase in dose.
Antibiotics such as penicillins, glycopeptides, sulphonamides, ciprofloxacin and cefalotin can in individual cases reduce the renal clearance of methotrexate, so that increased serum methotrexate concentrations can occur, accompanied by haematological and gastrointestinal toxicity. Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antibiotics may reduce intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting intestinal flora or suppressing bacterial metabolism.
In the event of (prior) treatment with medicinal products that can have adverse reactions on bone marrow (e.g. sulphonamides, trimethoprim/sulphamethoxazole, chloramphenicol, pyrimethamine), the possibility of haematopoietic disorders must be considered.
Concomitant therapy with medicinal products that can cause folic acid deficiency (e.g. sulphonamides, trimethoprim/sulphamethoxazole) can result in increased methotrexate toxicity. Accordingly, particular caution should be exercised in patients with pre-existing folic acid deficiency.
Conversely, co-administration of medicinal products containing folinic acid or vitamin preparations containing folic acid or derivatives may impair the efficacy of methotrexate.
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.
Ciclosporin 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 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.
Co-administration of proton pump inhibitors such as omeprazole or pantoprazole can result in interactions: co-administration of methotrexate and omeprazole has resulted in delayed renal elimination of methotrexate. In one case in which methotrexate was combined with pantoprazole, renal elimination of the metabolite 7-hydroxymethotrexate was inhibited and myalgia and shivering occurred.
The application of procarbazine during high-dose methotrexate therapy increases the risk of impairment or renal function.
Excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeinated beverages, black tea) should be avoided during methotrexate therapy as the effect of methotrexate may be reduced by the possible interaction between methotrexate and methylxanthines at the adenosine receptors.
Combination therapy with methotrexate and leflunomide may increase the risk for pancytopenia.
Particularly in the case of orthopaedic surgery where the risk of infection is high, combination therapy with methotrexate and immunomodulatory medicinal products must be used with caution.
Cholestyramine can increase the non-renal elimination of methotrexate by interfering with the enterohepatic circulation.
The possibility of delayed methotrexate clearance should be considered in combination with other cytostatic medicinal products.
Radiotherapy during the use of methotrexate can increase the risk for soft tissue or bone necrosis.
Methotrexate can reduce the clearance of theophylline. During concomitant therapy with methotrexate, therefore, serum theophylline levels should be monitored.
Combined administration of mercaptopurine and methotrexate can increase the bioavailability of mercaptopurine, possibly as a result of inhibition of the metabolism of mercaptopurine.
In view of its possible effects on the immune system, methotrexate can falsify vaccinal and test results (immunological procedures to assess the immune reaction). During methotrexate therapy, concurrent vaccination with live vaccines should be avoided (see sections 4.3 and 4.4).
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.
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 [15 ml]/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.
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.
Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg (15 ml)/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.
As methotrexate passes into breast milk and may cause toxicity in breast-fed children, treatment is contraindicated during the lactation period (see section 4.3). If use during the lactation period should become necessary, breast-feeding is to be stopped prior to treatment.
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).
Methotrexate has moderate influence on the ability to drive and use machines, since central nervous system disorders such as tiredness, dizzy spells or drowsiness can occur during treatment.
In general, the incidence and severity of side effects are considered to be dose-related.
In the antineoplastic treatment, myelosuppression and mucositis are the predominant dose-limiting toxic effects of methotrexate. The severity of these reactions depends on the dose, mode and duration of application of methotrexate. Mucositis generally appears about 3 to 7 days after methotrexate application, leucopenia and thrombocytopenia follow a few days later. In patients with unimpaired elimination mechanisms, myelosuppression and mucositis are generally reversible within 14 to 28 days.
Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and StevensJohnson syndrome.
Most frequently (very common) 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 (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus.
The occurrence and severity of adverse reactions depend on dosage level and frequency of administration of methotrexate. However, as severe adverse reactions may occur even at low doses, it is essential for the treating physician to monitor patients closely (see section 4.4).
Most adverse reactions are reversible if they are detected early. If such adverse reactions occur, the dose should either be reduced or treatment discontinued and appropriate countermeasures taken (see section 4.9). 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.
Frequencies in the table are defined according to the MedDRA 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)
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| System organ class | Very common | Common | Uncommon | Rare | Very rare | Not known |
|---|---|---|---|---|---|---|
| Infections and infestations | Infections | Opportunistic infections (sometimes fatal) | Herpes zoster | Sepsis, Cytomegalovirus induced infections | Nocardiosis, Histoplasma and cryptococcus mycosis, Disseminated herpes simplex | |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Lymphoma1 | |||||
| Blood and lymphatic system disorders | Leucocytopenia, Thrombocytopenia, Anaemia | Pancytopenia, Agranulocytosis, Haematopoietic disorders | Megaloblastic anaemia | Bone marrow depression (severe courses), Aplastic anaemia, Lymphoproliferative disorder2, Eosinophilia, Neutropenia, Lymphadenopathy | Haemorrhages | |
| Immune system disorders | Allergic reactions, Anaphylactic shock, Fever, Chills | Immunosuppression, Allergic vasculitis (severe toxic symptom), Hypogammaglobulinaemia | ||||
| Metabolism and nutrition disorders | Diabetes mellitus | |||||
| Psychiatric disorders | Depression | Mood swings | Insomnia | |||
| Nervous system disorders | Headache, Fatigue, Drowsiness | Convulsions, Vertigo, Confusion | Hemiparesis, Paresis | Cerebral oedema, Acute aseptic meningitis with meningism (paralysis, vomiting), Lethargy, Transient subtle cognitive dysfunction, Psychoses, Aphasia, Pain, Muscular asthenia,Paraesthesia / hypoaesthesia, Taste changes (metallic taste), Irritation, Dysarthria, Unusual cranial sensations, Tinnitus | Encephalopathy/Leukoencephalopathy | |
| Eye disorders | Severe visual disturbances | Retinopathy, Conjunctivitis | ||||
| Cardiac disorders | Pericarditis, Pericardial effusion, Pericardial tamponade | |||||
| Vascular disorders | Thromboembolic reactions (including arterial and cerebral thrombosis, thrombophlebitis, deep leg vein thrombosis, retinal vein thrombosis, pulmonary embolism), Hypotension | |||||
| Respiratory, thoracic and mediastinal disorders | Interstitial alveolitis/ pneumonia (can be fatal) | Pulmonary fibrosis | Respiratory paralysis, Bronchial asthma-like reactions such as cough, dyspnoea and pathological changes in lung function tests, Pharyngitis | Pneumocystis jiroveci pneumonia and other lung infections, Chronic obstructive pulmonary disease, Pleural effusion | Pulmonary alveolar haemorrhage3 | |
| Gastrointestinal disorders | Loss of appetite, Nausea, Vomiting, Abdominal pain, Inflammation and ulceration of mucosa of mouth and throat, Stomatitis, Dyspepsia | Diarrhoea | Ulceration and bleeding of gastrointestinal tract | Pancreatitis, Enteritis, Malabsorption, Melaena, Gingivitis | Toxic megacolon, Haematemesis | |
| Hepatobiliary disorders | Increase in liver-related enzymes (ALAT [GPT], ASAT [GOT], alkaline phosphatase and bilirubin) | Hepatic steatosis, fibrosis and cirrhosis, Decrease in serum albumin | Acute hepatitis and hepatotoxicity | Acute liver degeneration, Liver failure, Reactivation of chronic hepatitis | Hepatitis and liver failure4 | |
| Skin and subcutaneous tissue disorders | Erythema, Exanthema, Pruritus | Severe toxic manifestations: vasculitis, herpetiform skin eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), Increased rheumatic nodules, Painful erosions of psoriatic plaque, Photosensitivity, Increased skin pigmentation, Hair loss, Impaired wound healing, Urticaria | Increased nail pigment changes, Onycholysis, Acne, Petechiae, Bruising, Erythema multiforme, Cutaneous erythematous eruptions, Lesions of psoriasis may worsen with concomitant UV therapy, Radiation dermatitis and sunburn may be "recalled" | Acute paronychia, Furunculosis, Telangiectasis, Hidradenitis | Skin exfoliation/dermatitis exfoliative | |
| Musculoskeletal and connective tissue disorders | Osteoporosis, Arthralgia, Myalgia | Stress fracture | Osteonecrosis of jaw (secondary to lymphoprolifer-ative disorders) | |||
| Renal and urinary disorders | Nephropathy Inflammation and ulceration of urinary bladder (possibly with haematuria), Dysuria | Renal failure, Oliguria, Anuria, Azotaemia | Proteinuria | |||
| Reproductive system and breast disorders | Vaginal Inflammation and ulceration | Oligospermia, Menstrual dysfunction | Infertility, Loss of libido, Impotence, Vaginal discharge, Gynaecomastia | |||
| General disorders and administration site conditions | Fever | Oedema |
1 can be reversible – see 4.4
2 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.
3 has been reported for methotrexate used in rheumatologic and related indications
4 see remarks on liver biopsy in section 4.4
Frequency, type and severity of adverse reactions in children and adolescents are expected to be the same as in adults.
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 national reporting system listed in Appendix V.
Not applicable.
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