ARX-METHOTREXATE

What it is

Methotrexate Accord is a solution for injection containing methotrexate , available in multiple formulations. Each millilitre contains either 25 mg methotrexate or 100 mg methotrexate, supplied in vials of 2 mL (50 mg total) or 10 mL (1000 mg total) . Methotrexate Accord is a sterile yellow to orange solution for injection .

Approved indications

— Breast cancer, gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole — Acute leukaemias in combination with other chemotherapeutic agents, particularly acute lymphoblastic leukaemia — Burkitt's lymphoma (advanced stages III and IV), lymphosarcoma (advanced stages, especially in children), and advanced mycosis fungoides — High-dose therapy for epidermoid cancers of the head and neck, osteogenic sarcoma and bronchogenic carcinoma — Severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of treatment

Dosing overview

Dosing varies substantially by indication and route of administration. For trophoblastic neoplasms, methotrexate is administered intramuscularly in doses of 15 mg to 30 mg daily for a five-day course, with repeat courses after one or more weeks; three to five courses are usually employed . For breast carcinoma, methotrexate dosage is 40 mg/m² intravenously on the first and eighth days . For lymphoblastic leukaemia induction, doses of 3.3 mg/m² orally combined with prednisolone are used; maintenance dosage of 30 mg/m² intramuscularly twice weekly is given after remission . For psoriasis, the recommended weekly single dose schedule is 10 to 25 mg intramuscularly or intravenously per week until adequate response is achieved, not exceeding 50 mg weekly . For intrathecal administration in meningeal leukaemia prophylaxis, only preservative-free methotrexate is used at doses dependent on age: less than 1 year (6 mg), 1 year (8 mg), 2 years (10 mg), and 3 years or older (12 mg) .

Key safety warnings

Methotrexate must only be used by physicians experienced in anti-metabolite chemotherapy, or in the case of non-oncological conditions, by a specialist physician. Because of the possibility of fatal or severe toxic reactions the patient should be fully informed by the physician of the risks involved and should be under constant supervision . Deaths have been reported with the use of methotrexate . Methotrexate may produce marked depression of the bone marrow, anaemia, aplastic anaemia, leucopenia, neutropenia, thrombocytopenia and bleeding . Methotrexate may be hepatotoxic particularly at high dosage or with prolonged therapy; liver atrophy, necrosis, cirrhosis, fatty changes and periportal fibrosis have been reported. Since changes may occur without previous signs of gastro-intestinal or haematological toxicity, hepatic function must be determined prior to initiation of treatment and monitored regularly throughout therapy . Potentially fatal opportunistic infections, especially *Pneumocystis jirovecii* pneumonia, may occur with methotrexate therapy . Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur . Pulmonary toxicity including acute or chronic interstitial pneumonitis and pulmonary fibrosis, which can progress rapidly and is potentially fatal, has been associated with methotrexate therapy. It may occur acutely at any time during therapy and has been reported at low doses . Methotrexate has caused foetal death and/or congenital anomalies. It is not recommended in women of child bearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks .

Contraindications

Methotrexate is contraindicated in patients with severe renal impairment . In the treatment of psoriasis, methotrexate is contraindicated in pregnant women and in patients with poor nutritional status, bone marrow depression, hepatic disorders or in those with pre-existing blood dyscrasias such as bone marrow hypoplasia, leucopenia, thrombocytopenia or anaemia . Methotrexate is contraindicated in patients with overt or laboratory evidence of immunodeficiency syndrome(s) . Breast feeding is contraindicated in women taking methotrexate . Methotrexate is contraindicated in patients with active, infectious disease or psoriasis patients with serious infections, and in psoriasis and rheumatoid arthritis patients with peptic ulcer disease or ulcerative colitis . The combination of methotrexate and acitretin is contraindicated .