EBETREX

Important warning about the dosage of Ebetrex:

In the treatment of rheumatoid arthritis, juvenile idiopathic arthritis (JIA) and psoriasis, methotrexate must only be used once a week. Dosage errors in the use of Ebetrex can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

Ebetrex should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Ebetrex is injected once weekly. It must be explicitly pointed out to the patient that Ebetrex is applied only once a week.

It is recommended to specify a certain day of the week as “day for injection”. Patients must be educated and trained in the proper injection technique when self- administering methotrexate. The first injection of Methotrexate should be performed under direct medical supervision.

5 mg of methotrexate once weekly, administered subcutaneously, intramuscularly or intravenously. Depending on the individual activity of disease and patient tolerability, the initial dose may be increased. A weekly dose of 25 mg should in general not be exceeded.

However, doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression. Response to treatment can be expected after approximately 4 - 8 weeks. Once the desired therapeutic result has been achieved, dose should be reduced gradually to the lowest possible effective maintenance dose.

Dose in children and adolescents below 16 years 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 dose may be increased up to 20mg/m² body surface area/week.

However, an increased monitoring frequency is indicated if the dose is increased. Due to limited data availability about intravenous use in children and adolescents, parenteral administration is limited to subcutaneous and intramuscular injection.

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.

Occurrence and severity of undesirable effects depend on dose level and frequency of Ebetrex administration. However, as severe adverse reactions may occur even at lower doses, it is indispensable that the doctor monitors patients regularly at short intervals.

Most undesirable effects are reversible if recognised early. 9). Methotrexate therapy should only be resumed with caution, under close assessment of the necessity for treatment and with increased alertness for possible reoccurrence 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 in the following table. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness The following adverse reactions may occur: Very common Common Uncommon Rare Very rare Not known Infections and infestations Herpes zoster Sepsis Herpes simplex, hepatitis opportunistic infections (may be fatal in some cases), lethal sepsis, histoplasma and cryptococcus mycosis nocardiosis, disseminated herpes simplex, infections caused by the cytomegaly virus including Very common Common Uncommon Rare Very rare Not known pneumonia, reactivation of a hepatitis B infection and worsening of a hepatitis C infection.

Neoplasms benign, malignant and unspecified (incl cysts and polyps) Individual cases of lymphoma1, Blood and lymphatic system disorders Leukocyto penia thrombocyt o-penia, anaemia Pancytopeni a, agranulocyto sis, haematopoie tic disorders Megaloblasti c anaemia Severe courses of bone marrow depression, aplastic anaemia.

lymphoprolifera tive disorders (see “description” below) Lymphadenopat hy, eosinophilia and neutropenia2. Immune system disorders Severe allergic reactions up to anaphylactic shock Hypogammaglo bulinaemia Immunosuppres sion, fever3), allergic vasculitis Metabolis m and nutrition disorders Diabetes mellitus Psychiatric disorders Depression Mood fluctuations, transient perception disorders Nervous system disorders Headache, fatigue, drowsiness, paraesthesi a Hemiparesis, vertigo, confusion, seizures, leukoenceph alopathy/enc ephalopathy (in parenteral Paresis, speech disorders including dysarthria and aphasia Pain, myasthenia in the extremities, dysgeusia (metallic taste), acute aseptic meningitis, meningism (paralysis, Very common Common Uncommon Rare Very rare Not known administratio n) vomiting), paraesthesia/ hypoaesthesia Eye disorders Severe visual disturbances (blurred or cloudy vision), severe dysopia of unknown aetiology Conjunctivitis, Cardiac disorders Hypotension Pericarditis, pericardial effusion, pericardial tamponade Vascular disorders Vasculitis (as severe toxic symptom) thromboemb olic events4 Respiratory , thoracic and mediastinal disorders Pulmonary complicatio ns due to interstitial alveolitis/p neumonitis and related deaths5 Pulmonary fibrosis, pleural effusion Pharyngitis, respiratory arrest Pneumocystis carinii pneumonia chronic obstructive pulmonary disease.

Patients must be clearly advised that the therapy is to be administered once a week, and not every day. Incorrect intake of methotrexate can lead to severe, including potentially lethal, side effects. Health personal and patients should be clearly instructed.

Particularly in elderly patients fatal outcomes have been reported with accidentally daily administration of the weekly dose. 5). Renal function In the presence of risk factors, such as – even borderline – impaired renal function, concomitant administration of non-steroidal antiphlogistics is not recommended (increased toxicity possible).

2). As methotrexate is predominantly excreted via the renal route, increased concentrations can be expected in cases of renal impairment, which may result in severe adverse reactions such as impaired renal function up to renal failure.

In connection with the administration of non-steroidal anti-inflammatory drugs, severe side effects including deaths have been reported. During therapy with methotrexate, exacerbation of renal function may develop with an increase in certain laboratory values (creatinine, urea and uric acid in serum).

Gastrointestinal toxicity Conditions leading to dehydration (emesis, diarrhoea, stomatitis) may also potentiate the toxicity of methotrexate due to elevated agent levels. In these cases use of methotrexate should be interrupted until the symptoms cease.

Methotrexate and pleural effusion/ascites In patients with pathological accumulation of liquid in body cavities (“third space”), such as ascites or pleural effusions, the plasma elimination half-life of methotrexate is prolonged resulting in unexpected toxicity.

Pleural effusions and ascites should be drained prior to initiation of methotrexate treatment. Increased caution should generally be exercised in patients with insulin-dependent diabetes mellitus as well as pulmonary function impairment.

3. Elderly Dose reduction should be considered in elderly patients due to reduced liver and kidney function as well as lower folate reserves which occurs with increased age. 4).

Duration and method of administration:

The medicinal product is for single use only. Ebetrex solution for injection can be injected via the intramuscular, intravenous or subcutaneous route (in children and adolescents only subcutaneous or intramuscular). In adults, intravenous administration should be given as a bolus injection.

6. The overall duration of treatment is decided by the doctor. The solution is to be visually inspected prior to use. Only clear solutions practically free from particles should be used. Any contact of methotrexate with skin and mucosa is to be avoided!

In case of contamination, the affected parts are to be rinsed immediately with plenty of water! 6. Ebetrex treatment of rheumatoid arthritis, juvenile idiopathic arthritis, severe psoriasis vulgaris and psoriatic arthritis represents long-term treatment.

Rheumatoid arthritis Treatment response in patients with rheumatoid arthritis can be expected after 4-8 weeks. Symptoms may return after treatment discontinuation. Severe forms of psoriasis vulgaris and psoriatic arthritis Response to treatment can generally be expected after 2-6 weeks.

Depending on the clinical picture and the changes of laboratory parameters, the therapy is then continued or discontinued.

Note:

When switching from oral use to parenteral use, a reduction in the dose may be required, due to the variable bioavailability of methotrexate after oral administration. Folic acid or folinic acid supplementation may be considered in accordance with current therapeutic guidelines.