Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany, Tel.: +49 4103 8006-0, Fax: +49 4103 8006-100
Metoject PEN is contraindicated in the case of:
Patients must be clearly informed that the therapy has to be administered once a week, not every day.
Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Therefore treatment with methotrexate should only be initiated and supervised by physicians whose knowledge and experience includes the use of antimetabolite therapy. Because of the possibility of severe or even fatal toxic reactions, the patient should be fully informed by the physician of the risks involved and the recommended safety measures.
Before beginning or reinstituting methotrexate therapy after a rest period
Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest x-ray and renal function tests. If clinically indicated, exclude tuberculosis and hepatitis.
During therapy (at least once a month during the first six months and every three months thereafter)
An increased monitoring frequency should be considered also when the dose is increased.
1. Examination of the mouth and throat for mucosal changes
2. Complete blood count with differential blood count and platelets. Haemopoietic suppression caused by methotrexate may occur abruptly and with apparently safe doses. Any profound drop in white-cell or platelet counts indicates immediate withdrawal of the medicinal product and appropriate supportive therapy. Patients should be advised to report all signs and symptoms suggestive of infection. Patients taking haematotoxic medicinal products (e.g. leflunomide) simultaneously should be monitored closely with blood count and platelets.
3. 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. 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. Further research is needed to establish whether serial liver chemistry tests or propeptide of type III collagen can detect hepatotoxicity sufficiently. The evaluation should be performed case by case and 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 medicinal products or chemicals and prolonged Methotrexate treatment or cumulative doses of 1.5 g or more.
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).
4. Renal function should be monitored by renal function tests and urinalysis (see sections 4.2 and 4.3).
As methotrexate is eliminated mainly by renal route, increased serum concentrations are to be expected in the case of renal impairment, which may result in severe undesirable effects.
Where renal function may be compromised (e.g. in the elderly), monitoring should take place more frequently. This applies in particular when medicinal products are administered concomitantly that affect the elimination of methotrexate, cause kidney damage (e.g. non-steroidal anti-inflammatory medicinal products) or that can potentially lead to impairment of blood formation. Dehydration may also intensify the toxicity of methotrexate.
5. Assessment of respiratory system: Alertness for symptoms of lung function impairment and, if necessary lung function test. Pulmonary affection requires a quick diagnosis and discontinuation of methotrexate. Pulmonary symptoms (especially a dry, non-productive cough) or a non-specific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnoea, hypoxemia, and an infiltrate on chest X-ray, infection needs to be excluded. This lesion can occur at all doses.
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.
6. Methotrexate may, due to its effect on the immune system, impair the response to vaccination results and affect the result of immunological tests. Particular caution is also needed in the presence of inactive, chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) for reasons of possible activation. Vaccination using live vaccines must not be carried out under methotrexate therapy.
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.
Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.
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.
Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions). Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration. Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment (see section 5.2).
Diarrhoea and ulcerative stomatitis can be toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.
For the treatment of psoriasis, methotrexate should be restricted to moderate to severe psoriasis which is not adequately responsive to topic forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.
Encephalopathy/leukoencephalopathy have been reported in oncologic patients receiving methotrexate therapy and cannot be excluded for methotrexate therapy in non-oncologic indications.
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.
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 Metoject PEN 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.
Use in children <3 years of age is not recommended as insufficient data on efficacy and safety is available for this population (see section 4.2).
The use of nitrous oxide potentiates the effect of methotrexate on folate, 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.
The probability of methotrexate exhibiting a hepatotoxic effect is increased by regular alcohol consumption and when other hepatotoxic medicinal products are taken at the same time (see section 4.4). Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide) should be monitored with special care. The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide, azathioprine, retinoids, sulfasalazine). The incidence of pancytopenia and hepatotoxicity can be increased when leflunomide is combined with methotrexate.
Combined treatment with methotrexate and retinoids like acitretin or etretinate increases the risk of hepatotoxicity.
Oral antibiotics like tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics can interfere with the enterohepatic circulation, by inhibition of the intestinal flora or suppression of the bacterial metabolism.
Antibiotics, like penicillines, 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.
Methotrexate is plasma protein bound and may be displaced by other protein bound medicinal products such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and acidic anti-inflammatory agents, which can lead to increased toxicity when used concurrently.
Probenecid, weak organic acids such as loop diuretics, and pyrazoles (phenylbutazone) can reduce the elimination of methotrexate and higher serum concentrations may be assumed inducing higher haematological toxicity. There is also a possibility of increased toxicity when low-dose methotrexate and non-steroidal anti-inflammatory medicinal products or salicylates are combined.
In the case of medication with medicinal products which may have adverse reactions on the bone marrow (e.g. sulphonamides, trimethoprim-sulphamethoxazole, chloramphenicol, pyrimethamine); attention should be paid to the possibility of pronounced impairment of blood formation.
The concomitant administration of products which cause folate deficiency (e.g. sulphonamides, trimethoprim-sulphamethoxazole) can lead to increased methotrexate toxicity. Particular care is therefore advisable in the presence of existing folic acid deficiency.
Vitamin preparations or other products containing folic acid, folinic acid or their derivatives may decrease the effectiveness of methotrexate.
An increase in the toxic effects of methotrexate is, in general, not to be expected when Metoject PEN is administered simultaneously with other antirheumatic medicinal products (e.g. gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, azathioprin, cyclosporin).
Although the combination of methotrexate and sulfasalazine can cause an increase in efficacy of methotrexate and as a result more undesirable effects due to the inhibition of folic acid synthesis through sulfasalazine, such undesirable effects have only been observed in rare individual cases in the course of several studies.
Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and mercaptopurine may therefore require dose adjustment.
Concomitant administration of proton-pump inhibitors like omeprazole or pantoprazole can lead to interactions: Concomitant administration of methotrexate and omeprazole has led to delayed renal elimination of methotrexate. In combination with pantoprazole inhibited renal elimination of the metabolite 7-hydroxymethotrexate 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.
An excessive consumption of caffeine- or theophylline-containing beverages (coffee, caffeine-containing soft drinks, black tea) should be avoided during methotrexate therapy.
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/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/week, but higher rates of spontaneous abortions and congenital malformations are expected.
When methotrexate was discontinued prior to conception, normal pregnancies have been reported.
Methotrexate is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants, Metoject PEN is contraindicated during breast-feeding (see section 4.3). Therefore breast-feeding must be discontinued prior and during administration.
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.
Metoject PEN has minor or moderate influence on the ability to drive and use machines.
Central nervous system symptoms such as tiredness and dizziness can occur during treatment.
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 (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 ALAT, 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 most relevant undesirable effects are suppression of the haematopoietic system and gastrointestinal disorders.
The following headings are used to organise the undesirable effects in order of frequency:
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)
Uncommon: Pharyngitis.
Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis.
Very rare: Lymphoma (see “description” below).
Common: Leukopenia, anaemia, thrombopenia.
Uncommon: Pancytopenia.
Very rare: Agranulocytosis, severe courses of bone marrow depression, lymphoproliferative disorders (see “description” below).
Not known: Eosinophilia
Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.
Uncommon: Precipitation of diabetes mellitus.
Uncommon: Depression, confusion.
Rare: Mood alterations.
Common: Headache, tiredness, drowsiness.
Uncommon: Dizziness.
Very rare: Pain, muscular asthenia or paraesthesia in the extremities, changes in sense of taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis.
Not known: Encephalopathy/leukoencephalopathy.
Rare: Visual disturbances.
Very rare: Impaired vision, retinopathy.
Rare: Pericarditis, pericardial effusion, pericardial tamponade.
Rare: Hypotension, thromboembolic events.
Common: Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, short of breath and fever.
Rare: Pulmonary fibrosis, Pneumocystis carinii pneumonia, shortness of breath and bronchial asthma, pleural effusion.
Not known: Epistaxis, pulmonary alveolar haemorrhage.
Very common: Stomatitis, dyspepsia, nausea, loss of appetite, abdominal pain.
Common: Oral ulcers, diarrhoea.
Uncommon: Gastrointestinal ulcers and bleeding, enteritis, vomiting, pancreatitis.
Rare: Gingivitis.
Very rare: Haematemesis, haematorrhea, toxic megacolon.
Very common: Abnormal liver function tests (increased ALAT, ASAT, alkaline phosphatase and bilirubin).
Uncommon: Cirrhosis, fibrosis and fatty degeneration of the liver, decrease in serum albumin.
Rare: Acute hepatitis.
Very rare: Hepatic failure.
Common: Exanthema, erythema, pruritus.
Uncommon: Photosensitisation, loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria.
Rare: Increased pigmentation, acne, petechiae, ecchymosis, allergic vasculitis.
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), increased pigmentary changes of the nails, acute paronychia, furunculosis, telangiectasia.
Uncommon: Arthralgia, myalgia, osteoporosis.
Rare: Stress fracture.
Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders).
Uncommon: Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.
Rare: Renal failure, oliguria, anuria, electrolyte disturbances.
Not known: Proteinuria.
Uncommon: Inflammation and ulceration of the vagina.
Very rare: Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge.
Rare: Fever, wound-healing impairment.
Not known: Asthenia.
The appearance and degree of severity of undesirable effects depends on the dose level and the frequency of administration. However, as severe undesirable effects can occur even at lower doses, it is indispensable that patients are monitored regularly by the doctor at short intervals.
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.
Subcutaneous application of methotrexate is locally well tolerated. Only mild local skin reactions (such as burning sensations, erythema, swelling, discolouration, pruritus, severe itching, pain) were observed, decreasing during therapy.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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