Methotrexate

Indications

Methotrexate is used for: Burkitt's lymphoma, Choriocarcinoma, Mycosis fungoides, Crohn's disease, Psoriasis, Osteosarcoma, Breast cancer, lymphosarcoma, Acute lymphoblastic leukaemia, Rheumatoid arthritis

Adult Dose

Adult: PO Burkitt's lymphoma 10-25 mg/day for 4-8 days, repeat after 7-10 days. Choriocarcinoma 15-30 mg/day for 5 days, repeat after an interval of at least 1 wk for 3-5 courses. Mycosis fungoides 2.5-10 mg/day to induce remission. Rheumatoid arthritis 7.5 mg once wkly, adjust if needed. Up to 20 mg/wk. Crohn's disease 12.5-22.5 mg once wkly for up to 1 yr. PO/IV/IM Psoriasis 10-25 mg once wkly, adjust subsequent doses if needed. IV Osteosarcoma 12-15 g/m2 as infusion, followed by folinic acid. Breast cancer 10-60 mg/m2 often w/ cyclophosphamide and fluorouracil. Advanced lymphosarcoma Up to 30 mg/kg, followed by folinic acid rescue. Acute lymphoblastic leukaemia Maintenance: 2.5 mg/kg every 14 days. PO/IM Acute lymphoblastic leukaemia Maintenance: 15 mg/m2 1-2 times/wk w/ other agents. IM Choriocarcinoma 15-30 mg/day for 5 days. Repeat after at least 1 wk for 3-5 courses. Mycosis fungoides 50 mg/wk in 1-2 divided doses. Crohn's disease 25 mg once wkly for 16 wk. Maintenance: 15 mg/wk. Intrathecal Meningeal leukaemia 12 mg/m2 (Max: 15 mg) once wkly for 2-3 wk, then once mthly. Hepatic impairment Bilirubin 3.1-5.0 mg/dL or AST > 3 times ULN: Give 75% of dose Bilirubin >5.0 mg/dL: Avoid use

Child Dose

Polyarticular Juvenile Idiopathic Arthritis Initial: 10 mg/m² PO/IM/SC qWeek Meningeal Leukemia <1 year: 6 mg intrathecally (IT) every 2-5 days 1-2 years: 8 mg IT every 2-5 days 2-3 years: 10 mg IT every 2-5 days >3 years: 12 mg IT every 2-5 days

Renal Dose

Renal impairment: CrCl (ml/min) Dosage Recommendation 61-80 75% of dose 51-60 70% of dose 10-50 30-50% of dose <10 Avoid use Intermittent hemodialysis: 50% of dose at normal dosing interval Continuous renal replacement therapy: 50% of dose at normal dosing interval

Administration

Should be taken on an empty stomach. Best taken on an empty stomach. May be taken w/ meals to reduce GI discomfort. Avoid taking w/ milk-rich products. IV/IM Preparation Reconstitute with D5W or NS: 20-mg vial, up to 25 mg/mL; 1-g vial, up to 50 mg/mL May dilute further for IV infusion IV/IM Administration Administer by IM, IV push, or IV infusion Regular IV given with no more than 25 mg/mL IV push: Administered at 10 mg/min IV infusion (usually >100 mg): Administered over 30 minutes to 4 hours, or according to institutional protocol High-dose therapy (uses 1-g vial): Administered over 4 hours Specific dosing schemes vary, but high doses should be followed by leucovorin 24 hours after initiation of therapy to prevent toxicity

Contra Indications

Severe renal or hepatic impairment, pre-existing profound bone marrow suppression in patients with psoriasis or rheumatoid arthritis, alcoholic liver disease, AIDS, pre-existing blood dyscrasias, pregnancy (in patients with psoriasis or rheumatoid arthritis), breast-feeding.

Precautions

Hepatic or renal impairment, bone marrow depression, elderly, neonates. Ulcerative disorders of the GI tract. Monitor haematological, renal and hepatic function, and GI toxicity regularly. Lactation: Drug excreted in breast milk; do not nurse

Pregnancy-Lactation

Pregnancy Based on published reports and mechanism of action, can cause embryo-fetal toxicity and fetal death when administered to pregnant women Verify pregnancy status of females of reproductive potential before initiating Contraindicated in pregnant women with nonmalignant disease Contraception Females Can cause fetal harm when administered to pregnant women; Use effective contraception during and for 6 months after final dose Males Can cause chromosomal damage to sperm cells Advise males with female partners of reproductive potential to use effective contraception during and for at least 3 months after final dose Infertility Females: Can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy; unknown if infertility may be reversed in all affected females Males: Can cause oligospermia or infertility during and after cessation of therapy; unknown if infertility may be reversed in all affected males Lactation Limited published literature report the presence of methotrexate in human milk in low amounts; no information is available on the effects on breastfed infants or milk production Because of the potential for serious adverse reactions, including myelosuppression, from methotrexate in breastfed infants, advise women not to breastfeed during therapy and for 1 week after final dose

Interactions

Decreased effectiveness with folic acid and its derivatives. Potentially Fatal: Increased toxicity with NSAIDs and salicylates; probenecid; some penicillins; aminoglycosides neomycin and paromomycin; sulfonamides such as sulfafurazole and sulfamethoxazole; co-trimoxazole or trimethoprim; nephrotoxic agents (e.g. cisplatin); ciclosporin; etretinate. Synergistic enhancement of effects with fluorouracil. Increased bioavailability of mercaptopurine. Reduces serum-valproate concentrations. Reduced serum concentrations with colestyramine. Increased serum concentrations with omeprazole.

Adverse Effects

Side effects of Methotrexate : >10% Arachnoiditis with intrathecal administration, Subacute toxicity with intrathecal administration (paralysis of extremities, cranial nerve palsy, seizure or coma), Demyelinating encephalopathy with cranial irradiation or other systemic chemotherapy, Reddening of skin, Hyperuricemia, Ulcerative stomatitis, Glossitis, Gingivitis, Nausea and vomiting, Diarrhea, Anorexia, Intestinal perforation, Mucositis (dose-dependent), Leukopenia, Thrombocytopenia, Renal failure, Azotemia, Nephropathy, Pharyngitis 1-10% Alopecia, Photosensitivity, Rash, Abdominal distress, Malaise, Fatigue, Chills, fever, Decreased resistance to infection, Gastrointestinal hemorrhage, Myelosuppression, Disorders of lung, interstitial pneumonia (acute, chronic), Atrophy of liver, cirrhosis, hepatic fibrosis or necrosis, elevated liver function tests, hepatic failure Potentially Fatal: Pulmonary reactions (e.g. interstitial lung disease); neurotoxicity (e.g. leukoencephalopathy, paresis, demyelination) with intrathecal use; foetal deaths.

Mechanism of Action

Methotrexate is a folic acid antagonist that inhibits DNA synthesis. It irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis.