ZLATAL

Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy. Patients must be educated and trained in the proper injection technique when self- administering methotrexate.

The first injection of Zlatal should be performed under direct medical supervision. Important warning about the dosage of Zlatal (methotrexate) In the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis, psoriatic arthritis and Crohn’s disease requiring dosing once a week.

Zlatal (methotrexate) must only be used once a week. Dosage errors in the use of Zlatal (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. Depending on the individual activity of the 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, the dose should be reduced gradually to the lowest possible effective maintenance dose.

Dosage 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. Parenteral administration is limited to subcutaneous 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. 4).

Dosage in patients with psoriasis vulgaris and psoriatic arthritis:

It is recommended that a test dose of 5 - 10 mg be parenterally administered one week prior to initiation of therapy, in order to detect idiosyncratic adverse effects. 5 mg 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. Once the desired therapeutic result has been achieved, dose should be reduced gradually to the lowest possible effective maintenance 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 adult 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.

1).

Patients with renal impairment:

Methotrexate should be used with caution in patients with impaired renal function.

The dose should be adjusted as follows:

Patients with hepatic impairment: 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) For a full list of contraindications, see section

Occurrence and severity of undesirable effects depend on dose level and frequency of Methotrexate 25 mg/ml 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 Sepsis, infections (incl.

reactivation of inactive chronic infection) may be fatal in some cases Cardiac disorders Pericarditis, pericardial effusion, pericardial tamponade Blood and lymphatic system disorders Leukocytopenia thrombocytopenia, anaemia Pancytopenia, agranulocytosis, haematopoietic disorders Severe courses of bone marrow depression, aplastic anaemia.

Lymphadenopathy, lymphoproliferative disorders (partly reversible, see “description” below), eosinophilia and neutropenia. First signs for these life-threatening complications may be: fever, sore throat, ulcerations of oral mucosa, flu-like complaints, strong exhaustion, epistaxis and dermatorrhagia.

Use of methotrexate should be interrupted immediately if the number of blood cells significantly declines Immune system disorders Allergic reactions, anaphylactic shock Immunosuppression Hypogammaglobulin- aemia Metabolism and nutrition disorders Diabetes mellitus Psychiatric disorders Depression, confusion Mood fluctuations Insomnia Nervous system disorders Headache, fatigue, drowsiness Vertigo, seizures Pain, muscular asthenia, paraesthesia/hypoaesthe sia, changes in sense of taste (metallic taste), acute aseptic meningitis with meningism (paralysis, vomiting) Not known: leukoencephalopathy Eye disorders Severe visual disturbances Conjunctivitis, retinopathy Neoplasms benign, malignant and unspecified (incl cysts and polyps) Individual cases of lymphoma, which abated in a number of cases once methotrexate treatment had been discontinued.

In a recent study, it was not possible to establish that methotrexate therapy increases the incidence of lymphomas Vascular disorders Hypotension, thromboembolic events Respiratory, thoracic and mediastinal disorders Pulmonary complications due to interstitial alveolitis/pneumonitis and related deaths (independent of dose and duration of methotrexate treatment).

Typical symptoms may be: general illness; dry, irritating cough; shortness of breath progressing to rest dyspnoea, chest pain, fever. Pulmonary fibrosis Pharyngitis, apnoea, bronchial asthma-like reactions with cough, dyspnoe and pathological findings in the lung function test Pneumocystis carinii pneumonia and other pulmonary infections, chronic obstructive pulmonary disease.

Pleural effusion Not known: pulmonary alveolar haemorrhage. Gastrointestinal disorders Loss of appetite, nausea, vomiting, abdominal pain, inflammation and ulcerations of the mucous membrane of mouth and throat (especially during the first 24-48 hours after administration of Methotrexate 25 mg/ml).

Stomatitis, dyspepsia Stomatitis, dyspepsia Diarrhoea (especially during the first 24-48 hours after administration of Methotrexate 25 mg/ml). Gastrointestinal ulcers and bleeding. Enteritis, melaena Gingivitis, malabsorption Haematemesis, toxic megacolon Hepato- biliary disorders Increase in liver- related enzymes (ALAT [GPT], ASAT [GOT], alkaline phosphatase and bilirubin).

Development of liver fattening, fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes); drop of serum albumin. 4); severe toxic reactions: vasculitis, herpetiform eruption of the skin, Stevens- Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Increased pigmentary changes of nails, onycholysis, acne, petechiae, ecchymoses, erythema multiforme, cutaneous erythematous eruptions. acute paronychia, furunculosis, telangiectasia hidradenitis Not known: Skin exfoliation / dermatitis exfoliative Musculoskeletal system, connective tissue and bone disorders Arthralgia, myalgia, osteoporosis Stress fracture Not known: Osteonecrosis of jaw (secondary to lymphoproliferative disorders) Renal and urinary disorders Inflammation and ulceration of the urinary bladder (possibly with haematuria), dysuria.

Renal failure, oliguria, anuria, azotaemia Proteinuria General disorders and administration site conditions After intramuscular use of methotrexate, local adverse reactions (burning sensation) or damage (sterile formation of abscess, destruction of fatty tissue) can occur at the site of injection, disturbed wound healing.

Fever, Subcutaneous administration of methotrexate shows good local tolerance. Only mild local skin reactions, the number of which decreased in the course of treatment, have been observed so far. Not known: injection site necrosis, oedema.

Reproductive system and breast […]

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 personnel and patients should be clearly instructed.

Patients receiving therapy should be appropriately monitored, so that signs of possible toxic effects or adverse reactions can be recognised and assessed without delay. Hence, methotrexate should be only administered by, or under the supervision of, doctors whose knowledge and experience include the use of antimetabolite therapy.

Due to the risk of severe or even fatal toxic reactions, the patients should be thoroughly informed by the doctor about the risks (including early signs and symptoms of toxicity) and recommended safety measures. They are to be informed about the necessity to immediately consult the physician if symptoms of intoxication occur as well as about the subsequent necessary monitoring of symptoms of intoxication (including regular laboratory tests).

Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression. Skin and mucosal contacts with methotrexate are to be avoided. In the case of contamination, the parts concerned should be rinsed with plenty of water.

Fertility and reproduction Fertility 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.

Teratogenicity – Reproductive risk Methotrexate causes embryotoxicity, abortion and foetal defects in humans. 6). The absence of pregnancy must be confirmed before Zlatal 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

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. Zlatal can be injected via the subcutaneous route. 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. Methotrexate 25 mg/ml 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.

Crohn's Disease:

Response to treatment can be expected after approximately 8 to 12 weeks.

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.

6), - concurrent vaccination with live vaccines.