METHOFILL

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. If considered appropriate, the treating physician can, in selected cases, delegate subcutaneous administration to the patient.

Patients must be educated and trained in the proper injection technique when self-administering methotrexate. The first injection of Methofill should be performed under direct medical supervision. Methotrexate is injected once weekly.

The patient must be explicitly informed about the unusual fact that methotrexate is administered once a week only. It is advisable to determine an appropriate fixed day of the week for the injection. Methotrexate elimination is reduced in patients with a third distribution space (ascites, pleural effusions).

4). Important warning about the dosage of Methofill (methotrexate) Methofill (methotrexate) must only be used once a week for the treatment of Rheumatoid arthritis, Juvenile arthritis, Psoriatic arthritis, Psoriasis, Crohn’s disease.

Dosage errors in the use of Methofill (methotrexate) can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully. 5 mg of methotrexate once weekly, administered subcutaneously.

5 mg per week. A weekly dose of 25 mg should in general not be exceeded. However, doses exceeding 20 mg/week are associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4 – 8 weeks.

Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose. 75 m2 could not be treated with this product. 5 mg are required, another medical product should be used.

The recommended dose is 10-15 mg/m² body surface area (BSA)/once weekly. In therapy-refractory cases the weekly dosage may be increased up to 20mg/m2 body surface area/once weekly. However, an increased monitoring frequency is indicated if the dose is increased.

Patients with JIA should always be referred to a rheumatology specialist in the treatment of children/adolescents. Use in children < 3 years of age is not recommended as insufficient data on efficacy and safety is available for this population.

4) Dosage in patients with psoriasis vulgaris and psoriatic arthritis It is recommended that a test dose of 5 – 10 mg should be administered parenterally, one week prior to therapy to detect idiosyncratic adverse reactions. 5 mg of methotrexate once weekly, administered subcutaneously.

The dose is to be increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Doses exceeding 20 mg per week can be associated with significant increase in toxicity, especially bone marrow suppression.

Response to treatment can generally be expected after approximately 2 – 6 weeks. Upon achieving the therapeutically desired result, the dose should be reduced gradually to the lowest possible effective maintenance dose. Maximum weekly dose The dose should be increased as necessary but should in general not exceed the maximum recommended weekly dose of 25 mg.

In a few exceptional cases a higher dose might be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate as toxicity will markedly increase. Dosage in patients with Crohn’s Disease • Induction treatment: 25 mg/week administered subcutaneously.

Response to treatment can be expected after approximately 8 to 12 weeks. • Maintenance treatment: 15 mg/week administered subcutaneously. There is not sufficient experience in the paediatric population to recommend methotrexate for the treatment of Crohn’s Disease in this population.

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) Dose > 60 100 % 30 – 59 50 % < 30 Methotrexate must not be used See section

Summary of the safety profile Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome.

g. 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.

Tabulated list of adverse reactions 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).

Infections and infestations Uncommon:

Pharyngitis.

Rare:

Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis. Neoplasms benign, malignant and unspecified (including cysts and polyps) Very rare: There have been reports of individual cases of lymphoma which subsided in a number of cases once treatment with methotrexate had been discontinued.

In a recent study, it could not be established that methotrexate therapy increases the incidence of lymphomas.

Blood and lymphatic system disorders Common:

Leukopenia, anaemia, thrombopenia.

Uncommon:

Pancytopenia.

Very rare:

Agranulocytosis, severe courses of bone marrow depression, Lymphoproliferative disorders (see “description” below).

Not known:

Eosinophilia.

Immune system disorders Rare:

Allergic reactions, anaphylactic shock, hypogammaglobulinaemia.

Metabolism and nutrition disorders Uncommon:

Precipitation of diabetes mellitus.

Psychiatric disorders Uncommon:

Depression, confusion.

Rare:

Mood alterations.

Nervous system disorders Common:

Headache, tiredness, drowsiness.

Uncommon:

Dizziness.

Very rare:

Pain, muscular asthenia or Paraesthesia/hypoaesthesia, changes in sense of taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis.

Not known:

Encephalopathy / leukoencephalopathy.

Eye disorders Rare:

Visual disturbances.

Very rare:

Impaired vision, retinopathy.

Cardiac disorders Rare:

Pericarditis, pericardial effusion, pericardial tamponade.

Vascular disorders Rare:

Hypotension, thromboembolic events.

Respiratory, thoracic and mediastinal disorders Common:

Pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia. Symptoms indicating potentially severe lung injury (interstitial pneumonitis) are: dry, not productive cough, shortness of breath and fever.

Rare:

Pulmonary fibrosis, Pneumocystis jirovecii pneumonia, shortness of breath and bronchial asthma, pleural effusion.

Not known:

Epistaxis, Pulmonary alveolar haemorrhage.

Gastrointestinal disorders 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. 4) 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.

Skin and subcutaneous tissue disorders Common:

Exanthema, erythema, pruritus.

Uncommon:

Loss of hair, increase in rheumatic nodules, skin ulcer, herpes zoster, vasculitis, herpetiform eruptions of the skin, urticaria, photosensitivity reactions.

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.

Not known:

Skin exfoliation / dermatitis exfoliative.

Musculoskeletal and connective tissue disorders Uncommon:

Arthralgia, myalgia, osteoporosis.

Rare:

Stress fracture.

Unknown:

Osteonecrosis of jaw (secondary to lymphoproliferative disorders).

Renal and urinary disorders Uncommon:

Inflammation and ulceration of the urinary bladder, renal impairment, disturbed micturition.

Rare:

Renal failure, oliguria, anuria, electrolyte disturbances.

Not known:

Proteinuria.

Reproductive system and breast disorders Uncommon:

Inflammation and ulceration of the vagina.

Very rare:

Loss of libido, impotence, gynaecomastia, oligospermia, impaired menstruation, vaginal discharge.

General disorders and administration site conditions Rare:

Fever, wound-healing impairment.

Very rare:

Local damage (formation of sterile abscess, lipodystrophy) of injection site following intramuscular or subcutaneous administration.

Not known:

Asthenia, Injection site necrosis, Oedema. The appearance and degree of severity of undesirable effects depends on the dosage 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.

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.

Description of selected adverse reactions Lymphoma/Lymphoproliferative disorders: there have been reports of individual cases of lymphoma and other lymphoproliferative disorders which subsided in a number of cases once […]

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.

Recommended examinations and 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 The tests below must be conducted every week during the first two weeks, then every two weeks for the next month; afterwards, depending on leukocyte count and stability of the patient, at least once a month during the next six months and at least every three months thereafter.

An increased monitoring frequency should also be considered also when the dose is increased. Particularly elderly patients should be examined for early signs of toxicity in short intervals. 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. g. leflunomide) simultaneously should be monitored closely with blood count and platelets. 3.

Liver function tests:

Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies. Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %.

Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests.

Liver biopsy should be considered on an individual basis taking into account the patient’s comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include 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.

Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. 5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products.

Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases. 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.

g. in the elderly), monitoring should take place more frequently. g. non-steroidal anti-inflammatory medicinal products) or which 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.

Pulmonary diseases induced by methotrexate were not always completely reversible. 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 […]

3. 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. 5 μmol/l), methotrexate is contraindicated.

3. Use in elderly patients Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occur with increased age. 4). Duration and method of administration The medicinal product is for single use only.

Methofill solution for injection can only be given by subcutaneous route The overall duration of the treatment is decided by the physician. 6. Please note that all of the contents have to be used.

Note:

If changing from oral application to parenteral administration a reduction of the dose may be required due to the variable bioavailability of methotrexate after oral administration. Folic acid supplementation may be considered according to current treatment guidelines.

6), − concurrent vaccination with live vaccines.