Uses and Administration of Methotrexate in Kenya
Methotrexate is an antineoplastic which acts as an antimetabolite of folic acid. It also has immunosuppressant properties. Within the cell, folic acid is reduced to dihydrofolic and then tetrahydrofolic acid. Methotrexate competitively inhibits the enzyme dihydrofolate reductase and prevents the formation of tetrahydrofolate which is necessary for purine and pyrimidine synthesis and consequently the formation of DNA and RNA. It is most active against cells in the S phase of the cell cycle. Folinic acid (the 5-formyl derivative of tetrahydrofolic acid) has been given after high doses to bypass the block in tetrahydrofolate production in normal cells and prevent the adverse effects of methotrexate. Methotrexate, in very high doses, followed by folinic acid rescue, is used in treating some malignant diseases.
Methotrexate is used in the management of acute lymphoblastic leukaemia. It is seldom used for the induction of remission but is employed in maintenance programmes and in the prophylaxis and treatment of meningeal leukaemia. It may be used for Burkitt’s and other non-Hodgkin’s lymphomas. In the solid neoplasms it is an important part of curative regimens for choriocarcinoma and other gestational trophoblastic tumours, and for the adjuvant therapy of osteosarcoma and breast cancer. It may also be used in malignant neoplasms of the bladder and head and neck, and a variety of other neoplasms, as indicated by the cross references given below.
Methotrexate is of value in the treatment of psoriasis but because of the risks associated with this use, it should only be given when the disease is severe and has not responded to other forms of treatment. It is used widely as a disease-modifying antirheumatic drug in rheumatoid arthritis. Methotrexate may be used to prevent graft-versus-host disease after bone marrow transplantation and may be used as a cytotoxic immunosuppressant and corticosteroid-sparing agent in a variety of non-malignant diseases.
Methotrexate has a role in the management of ectopic pregnancy
Methotrexate has been given by local injection directly into the ectopic (salpingocentesis). Doses of 1 mg/kg or 50 mg have been used10 but this technique is significantly less successful than surgery.3 Systemic methotrexate (with folinic acid rescue) has also been reported to be effective in resolving persistent ectopic pregnancy unsuccessfully treated with surgery.
Methotrexate in Kenya may be given by mouth as the base or the sodium salt, or by injection as the sodium salt. Doses are calculated in terms of methotrexate. Methotrexate sodium 16.5 mg is approximately equivalent to 15 mg of methotrexate. The doses and regimens used vary enormously, and may need to be adjusted according to bone marrow or other toxicity (see also under Bone-marrow Depression, ). Doses larger than 100 mg are usually given partly or wholly by intravenous infusion over not more than 24 hours.
A common dose for maintenance therapy of acute lymphoblastic leukaemia in Kenya is 15 mg/m2 once or twice weekly, by mouth or intramuscularly, with other agents such as mercaptopurine. Alternatively, 2.5 mg/kg may be given intravenously every 14 days. Meningeal leukaemia may be treated by the intrathecal injection of 12 mg/m2 (maximum 15 mg) once weekly for 2 to 3 weeks, then once monthly; an alternative is 200 to 500 micrograms/kg at intervals of 2 to 5 days until the cell count of the CSF returns to normal. Another regimen has been recommended for children based on age, with children under the age of 1 year receiving 6 mg, 8 mg for those 1 year of age, 10 mg in 2-year-olds, and 12 mg in those 3 years of age or older. Intrathecal doses have also sometimes been given prophylactically to patients with lymphoblastic leukaemia in association with intrathecal cytarabine and hydrocortisone. Methotrexate in intravenous doses of about 500 mg/m2, followed by folinic acid rescue, may also produce effective concentrations in the CSF and has been used for meningeal leukaemia.
Choriocarcinoma has been treated with doses of 15 to 30 mg daily by mouth or intramuscularly for 5 days repeated after an interval of 1 week or more, for 3 to 5 courses. Alternatively 0.25 to 1 mg/kg up to a maximum of 60 mg has been given intramuscularly every 48 hours for 4 doses, followed by folinic acid rescue, and repeated at intervals of 7 days for 4 or more courses. Combination chemotherapy may be necessary in patients with metastases.
Doses of 10 to 60 mg/m2 are employed intravenously in the treatment of breast cancer, often with cyclophosphamide and fluorouracil.
In advanced lymphosarcoma doses of 0.625 to 2.5 mg/kg daily have been suggested with other antineoplastics. Alternatively, higher doses of up to 30 mg/kg have been given intravenously, followed by folinic acid rescue. For Burkitt’s lymphoma 10 to 25 mg of methotrexate has been given daily by mouth for 4 to 8 days, repeated after an interval of 7 to 10 days, while patients with mycosis fungoides may be given 2.5 to 10 mg daily by mouth to induce remission; alternatively 50 mg may be given weekly as a single dose or two divided doses, by intramuscular injection.
Very high doses, in the range 12 to 15 g/m2 have been given by intravenous infusion, followed by folinic acid, as part of combined adjuvant therapy in patients with osteosarcoma. High-dose regimens have been tried in a variety of other malignancies, including carcinoma of the lung and of the head and neck.
Single weekly doses of 10 to 25 mg may be given by mouth or by intramuscular or intravenous injection in the treatment of psoriasis and adjusted by response. Other, more frequent, regimens have been used but a weekly dosage regimen appears to be less hepatotoxic than a daily one. In the treatment of rheumatoid arthritis doses of 7.5 mg by mouth once weekly are used, adjusted by response and not exceeding 20 mg/week.
It is essential that blood counts and tests of renal and liver function should be made before, during, and after each course of treatment with methotrexate.
Methotrexate and Termination of pregnancy
Methotrexate has been investigated as an alternative to mifepristone for use with misoprostol for the termination of pregnancy. Intramuscular methotrexate followed 3 days later by intravaginal misoprostol was more effective than misoprostol alone for termination at 56 days or less;1 the combination was reported to be less successful after 57 to 63 days’ gestation.2 Later studies3,4 however found the combination to be safe and effective in terminating pregnancies up to 63 days’ gestation; in these the misoprostol was administered up to 7 days after the methotrexate. Oral methotrexate is also effective.5-7
Adverse Effects of Methotrexate in Kenya
The most common dose-related toxic effects of methotrexate are on the bone marrow and gastrointestinal tract. Bone-marrow depression can occur abruptly, and leucopenia, thrombocytopenia, and anaemia may all occur. The nadir of the platelet and white-blood cell counts is usually around 5 to 10 days after a bolus dose, with recovery between about 14 to 28 days, but some sources suggest that leucocytes may exhibit an early fall and rise, followed by a second nadir and recovery, within this period. Ulceration of the mouth and gastrointestinal disturbances are also early signs of toxicity: stomatitis and diarrhoea during treatment indicate that it may need to be interrupted, otherwise haemorrhagic enteritis, intestinal perforation, and death may follow.
Methotrexate is associated with liver damage, both acute (notably after high doses) and, more seriously, chronic (generally after long-term use). Hepatic fibrosis and cirrhosis may develop without obvious signs of hepatotoxicity, and have led to eventual death.
Other adverse effects include renal failure and tubular necrosis following high doses, pulmonary reactions including life-threatening interstitial lung disease, skin reactions (sometimes severe), alopecia, and ocular irritation. Neurotoxicity may be seen: leukoencephalopathy, paresis, demyelination are associated particularly with intrathecal use and are more likely when cranial irradiation is also given. Intrathecal administration may also produce arachnoiditis, an acute syndrome of headache, nuchal rigidity, back pain, and fever. Other rarer reactions may include megaloblastic anaemia, osteoporosis, precipitation of diabetes, arthralgias, necrosis of soft tissue and bone, and anaphylaxis.
Methotrexate may cause defective oogenesis and spermatogenesis, and fertility may be impaired (this may be reversible). Like other folate inhibitors it is teratogenic, and it has been associated with fetal deaths. Lymphomas (generally reversible on withdrawal of treatment) have occasionally been reported with methotrexate therapy, although the association has been questioned.