EBETREX

Important warning about the dosing of Ebetrex:

In the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis (JIA) and psoriasis Ebetrex (methotrexate) must only be used once a week. Dosage errors in the use of Ebetrex (methotrexate) can result in serious adverse reactions, including death.

Please read this paragraph 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 administered only once a week. The prescriber should specify the day of intake on the prescription. The administration should routinely be done by health professionals.

If the clinical situation permits the treating physician can, in selected cases, delegate the administration to the patient her/himself. In these cases, detailed administration instructions from the physician are obligate. Patients must be educated and trained in the proper injection technique when self-administering methotrexate.

The first injection of Ebetrex should be performed under direct medical supervision.

Dose in patients with rheumatoid arthritis:

It is recommended that a test dose is parenterally administered one week prior to initiation of therapy, in order to detect idiosyncratic adverse effects. 5 mg of methotrexate once weekly, administered subcutaneously, intramuscularly or intravenously.

5 mg per week. Alternatively a higher starting dose can be used. The average weekly dose is 15mg - 20mg Methotrexate. A weekly dose of 25 mg should 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. Symptoms might re-occur after stopping the treatment, Paediatric population Dose in children (> 3 years) 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 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.

5-5 mg is recommended for the assessment of toxicity. With unchanged laboratory parameters 1 week later continuation with approx. 5 mg. 5 mg per week) while monitoring the laboratory parameters until an optimal treatment result is achieved.

A weekly dose of 25 mg methotrexate should generally not be exceeded. Once the desired outcome has been achieved, the dose should, as far as possible, be gradually reduced to the lowest maintenance dose still effective in the individual patient.

Response to therapy generally occurs after 4-8 weeks. Thereafter, the therapy is continued or discontinued according to the clinical picture and laboratory parameter changes.

Patients with impaired renal function:

Ebetrex should be used with caution in patients with impaired renal function. The following table lists recommended baseline doses for patients with impaired renal function; due to pronounced inter-individual pharmacokinetic variability, further dose adjustment may be necessary.

Creatinine clearance (ml / min) % of the stated standard dose > 80 100 ~ 60-80 ~ 63-75 <60 Use of alternative therapy Patients with impaired hepatic function: Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially when caused by alcohol.

5 μmol/L). 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 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 […]

Incidence and severity of undesirable effects usually depend on dose level and frequency of methotrexate administration. As severe adverse reactions may occur even at lower doses and at any time during therapy, it is indispensable that the doctor monitors patients regularly at short intervals.

Most undesirable effects are reversible if recognised early. However, some of the severe adverse reactions named below may result in sudden death in very rare cases. 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.

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 liver 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 < 1/10), uncommon (≥ 1/1,000 < 1/100), rare (≥ 1/10,000 < 1/1,000), very rare (< 1/10,000) , not known (frequency cannot be estimated from the available data).

Very common Common Uncommon Rare Very rare Not known Infections and infestatio ns Herpes zoster Opportunist ic infections (may be fatal in some cases) Sepsis (including fatal) Herpes simplex, hepatitis, histoplasmos is, cryptococcos is, cytomegalovi rus infection (including pneumonia), disseminated herpes simplex, nocardiosis, pneumocystis -jirovecii pneumonia* Pneumonia, reactivation of a hepatitis B infection and worsening of a hepatitis C infection.

Neoplasm s benign, malignant and unspecifie d (incl. 5) Blood and lymphatic system disorders Thrombocyto penia, leukopenia Anaemia, pancytopenia, myelosuppress ion, agranulocytosi s Megaloblasti c anaemia Aplastic anaemia, eosinophilia, neutropenia, lymphadenop athy (partly reversible), lymphoprolif erative disorders (see “description” Very common Common Uncommon Rare Very rare Not known below).

Immune system disorders Allergic reactions, up to anaphylacti c shock, immunosup pression Hypogamma globulinaemi a Metabolis m and nutrition disorders Diabetes mellitus Psychiatri c disorders Depression Mood fluctuations, transient perception disorders Nervous system disorders Headache, vertigo Drowsiness, paraesthesia Hemiparesi s, confusion, seizures, leukoencep halopathy/ encephalop athy* Paresis, speech disorders including dysarthria and aphasia Pain and myasthenia in the extremities, dysgeusia (metallic taste), acute aseptic meningitis, meningism (paralysis, vomiting), cranial nerve syndrome, Paraesthesia/ hypoaesthesi a Neurotoxicity , arachnoiditis, paraplegia, stupor, ataxia, dementia, increase in the pressure of cerebrospinal fluid Eye disorders Conjunctivitis Visual disturbances, (partly severe), retinal vein thrombosis Periorbital oedema, blepharitis, epiphora, photophobia, transient blindness, loss of vision Retinopathy Cardiac disorders Pericarditis, pericardial effusion, pericardial tamponade Vascular disorders Vasculitis, allergic vasculitis.

Hypotension, thromboemb olic events (including arterial and cerebral thrombosis, thrombophle bitis, deep vein Very common Common Uncommon Rare Very rare Not known thrombosis), Respirator y, thoracic and mediastin al disorders Cough Pulmonary complications due to interstitial alveolitis/pneu monitis and related deaths (independent of dose and duration of methotrexate treatment).

Pulmonary fibrosis, pleural effusion Pharyngitis, respiratory arrest, pulmonary embolism Chronic interstitial pulmonary disease, asthma, bronchiale- like reactions with cough, dyspnoea, pathological findings in pulmonary function test.

Hypoxia, Pulmonary alveolar haemorrhage Gastrointe stinal disorders Loss of appetite, diarrhoea (particularly within the first 24 – 48 hours after administratio n of methotrexate ) nausea, vomiting, abdominal pain, inflammation and ulcerations of the mucous membrane of mouth and throat (especially during the first 24-48 hours after administratio n of methotrexate ).

Gastrointest inal ulcers and haemorrhag es, pancreatitis Enteritis, melaena gingivitis, Haematemesi s Non- infectious peritonitis, toxic megacolon, intestinal perforation, glossitis. 4) Increase in liver-related enzymes (ALAT [GPT], ASAT [GOT], alkaline phosphatase and bilirubin).

Hepatotoxic ity, hepatic steatosis, chronic hepatic fibrosis and hepatocirrh osis, drop of serum albumin. Acute hepatitis Acute liver necrosis, acute liver degeneration, hepatic failure Skin and subcutane ous tissue Alopecia Exanthema, erythema, pruritus, As severe toxic phenomena: Acne, petechiae, ecchymoses, Acute paronychia, furunculosis, Drug reaction with eosinophilia Very common Common Uncommon Rare Very rare Not known disorders photosensitivit y skin ulceration herpetiform eruption of the skin, Stevens- Johnson syndrome* toxic epidermal necrolysis (Lyell’s syndrome)* , urticaria, enhanced pigmentatio n of the skin, nodulosis, disturbed wound healing, painful lesions of psoriatic plaque erythema multiforme, cutaneous erythematous eruptions, increased pigmentary changes of nails, onycholysis.

telangiectasia , photosensitiv ity and systemic symptoms (DRESS) dermatitis. skin exfoliation / dermatitis exfoliative Musculos keletal system, connectiv e tissue and bone disorders Arthralgia, myalgia, osteoporosi s Stress fracture Osteonecrosis , osteonecrosis of jaw (secondary to lymphoprolife rative […]

Special warnings The prescriber should specify the day of intake on the prescription. The prescriber should make sure patients understand that methotrexate should only be taken once a week. Patients should be instructed on the importance of adhering to the once- weekly intakes.

9). Especially in the elderly, deaths were reported following the accidental daily use of the weekly dose. Methotrexate should only be prescribed by physicians who have sufficient experience in treating the disease with methotrexate.

Fertility and reproduction Fertility Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans during and for a short period after the discontinuation of treatment and to cause impaired fertility, 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. 6). The absence of pregnancy must be confirmed before methotrexate 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

6).