METHOTREXATE

WARNINGS

The dose must be adjusted carefully depending on the body surface area if methotrexate is used for the treatment of tumour diseases. Fatal cases of intoxication have been reported after administration of incorrectly calculated doses.

Health care professionals and patients should be fully informed about toxic effects. Treatment should be initiated by or occur in consultation with a doctor with significant experience in cytostatic treatment. Methotrexate can be administered intramuscularly, intravenously, intra-arterial or intrathecally.

The dosage is generally calculated per m2 body surface area or body weight. Doses of over 100 mg methotrexate always require subsequent administration of folinic acid (See calcium folinate rescue). The application and dosage recommendations for the administration of methotrexate for different indications varies considerably.

Some common dosages which have been used in different indications are given below. None of these dosages can currently be described as standard therapy. Since the application and dosage recommendations for therapy with methotrexate at high and low dosages vary, only the most commonly used guidelines are given, and should be considered as examples.

Current published protocols should be consulted for dosages and the method and sequence of administration. Posology Methotrexate can be given as convention low dose therapy, intermediate dose therapy, high dose therapy and intrathecal administration.

Conventional low dose therapy: 15-50 mg/m2 body surface area per week intravenously or intramuscularly in one or more doses. 40-60 mg/m2 body surface area (for head and neck cancer) once weekly as intravenous bolus injection.

Intermediate dose therapy:

Between 100 mg/m2 to 1000 mg/m2 body surface area in single dose. In advanced squamous epithelial and bladder cancer, intermediate doses of methotrexate up to 100- 200 mg/m2 can be used. (See Calcium folinate rescue).

High dose therapy:

In several malignant diseases, including malignant lymphoma, acute lymphatic leukaemia, osteogenic sarcoma and metastatic choriocarcinoma, doses of 1000 mg methotrexate or more per m2 body surface area may be used, administered over a 24-hour period.

Conventional and high dose therapy The frequency and degree of severity of undesirable effects depends on the dose administered, the duration of exposure and method of administration, but side effects have been seen at all doses and can occur at any time during treatment.

Most undesirable effects are reversible when detected at an early stage. 9). If treatment with methotrexate is resumed, this should be done with caution after adequate consideration of the further need for the drug. Increased vigilance with regard to any recurrence of toxicity is required.

The most frequently reported undesirable effects include ulcerative stomatitis, leukopenia, nausea and bloating. Other frequently reported undesirable effects are feeling unwell, unusual tiredness, chills and fever, dizziness, reduced resistance to infections.

Treatment with folinic acid during high dose therapy can counteract or alleviate a number of undesirable effects. Temporary discontinuation of therapy is recommended if there are signs of leukopenia. Organ system class 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 Herpes zoster Sepsis, opportunistic infections (may be fatal in some cases), infections caused by the cytomegaly virus Cardiac disorders Pericarditis pericardial effusion pericardial tamponade Blood and lymphatic system disorders leukocytopenia, thrombocytopenia and anaemia Pancytopenia agranulocytosis haematopoietic disorders Megaloblast ic anaemia Severe courses of bone marrow depression aplastic anaemia Lymphadenopath y , eosinophilia and neutropenia, Lympho- proliferative disorders Haemorrhag e, haematoma Immune system disorders Anaphylactoid reactions, allergic vasculitis Immunosuppressi on hypogammaglobu linaemia Psychiatric disorders Insomnia, cognitive dysfunction psychosis Nervous system disorders Headache fatigue drowsiness Vertigo confusion depression seizures convulsion encephalopathy Severely impaired vision mood alterations paresis, effect on speech including Pain, muscular asthenia or paresthesia of the extremities, myasthenia, changes in sense of taste (metallic taste), meningism (paralysis, dysarthria and aphasia, myelopathy vomiting), acute aseptic meningitis Eye disorders visual disturbances , blurred vision Conjunctivitis Retinopathy, transient blindness/loss of vision, periorbital oedema, blepharitis, epiphora, photophobia 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.

Fatal toxicity in association with intravenous and intrathecal administration due to dose miscalculation has been reported. 2). 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 methotrexate should only be administered by, or under the supervision of physicians whose knowledge and experience includes the use of antimetabolite therapy. Because of the risk of severe toxic reactions (which can be fatal), methotrexate must only be used in life-threatening neoplastic diseases.

Deaths have been reported during treatment of malignancies with methotrexate. The doctor should inform the patient of the risks of treatment and the patient should be monitored constantly by the doctor. 5). Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.

In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co- administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment. Cases of neurological side effects ranging from headache to paralysis, coma and stroke-like episodes have been reported, primarily in children and adolescents receiving concomitant medication with cytarabine.

Fertility Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans during and for a short period after the discontinuation of treatment, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy.

1. 2). Alcohol abuse. 2). Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia. Serious, acute or chronic infections such as tuberculosis and HIV. Ulcers of the oral cavity and known active gastrointestinal ulcer disease.

6). Concurrent vaccination with live vaccines.