Methotrexate

Indications

Oral
Burkitt's lymphoma
Adult: 10-25 mg daily for 4-8 days, repeated after 7-10 days.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Oral
Acute lymphoblastic leukaemia
Adult: Maintenance: 15 mg/m² once or twice wkly, with other agents.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Oral
Choriocarcinoma
Adult: 15-30 mg daily for 5 days, repeat after an interval of ≥1 wk for 3-5 courses.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Oral
Mycosis fungoides
Adult: 2.5-10 mg daily to induce remission.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Oral
Psoriasis
Adult: 10-25 mg wkly as a single dose, adjust subsequent doses based on response.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Oral
Rheumatoid arthritis
Adult: 7.5 mg once wkly, adjust by response. Not more than 20 mg/wk.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Oral
Crohn's disease
Adult: 12.5-22.5 mg once wkly for up to 1 yr.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of use
51-60	70% of use
10-50	30-50% of use
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intrathecal
Meningeal leukaemia
Adult: 12 mg/m² (max 15 mg) once wkly for 2-3 wk, then once mthly. Alternatively, 200-500 mcg/kg every 2-5 day until CSF cell count is normalised.
Child: <1 yr: 6 mg, 1 yr: 8 mg, 2 yr: 10 mg, >3 yr: 12 mg. Patients <3 yr should be treated in accordance with combination chemotherapy protocols. Admin is at wkly intervals and repeated until the CSF cell count is normal.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intravenous
Osteosarcoma
Adult: Initial recommended dose: 12 g/m² as a 4-hr infusion, followed by folinic acid, as part of combined therapy. May increase dose to 15 g/m² in subsequent treatments if initial dosage is insufficient to achieve peak serum methotrexate levels of 454 mcg/mL at the end of the infusion. Methotrexate infusion is administered on postoperative wk 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44 and 45; in combination with other chemotherapy agents. Folinic acid can be given orally, IM or IV inj starting 24 hr after the beginning of the methotrexate infusion. Give via parenteral routes If patient experiences GI toxicity (e.g., nausea, vomiting). Usual dosage of folinic acid: 15 mg every 6 hr for a total of 60 hr or a total of 10 doses.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intramuscular
Choriocarcinoma
Adult: 15-30 mg daily for 5 days. Repeat after at least 1 wk for 3-5 courses. Alternatively, 0.25-1 mg/kg (max: 60 mg) every 48 hr for 4 doses followed by folinic acid rescue, repeat at intervals of 7 days for 4 or more courses.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intravenous
Breast cancer
Adult: 10-60 mg/m² often with cyclophosphamide and fluorouracil.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intravenous
Advanced lymphosarcoma
Adult: Up to 30 mg/kg, followed by folinic acid rescue.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intramuscular
Acute lymphoblastic leukaemia
Adult: Maintenance: 15 mg/m² once or twice wkly, with other agents.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intravenous
Acute lymphoblastic leukaemia
Adult: Maintenance: 2.5 mg/kg every 14 days.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intramuscular
Mycosis fungoides
Adult: 50 mg wkly as a single dose or 2 divided doses.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Parenteral
Psoriasis
Adult: 10-25 mg wkly as a single dose. Adjust subsequent doses based on response. May be given via IV/IM admin.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.
Intramuscular
Crohn's disease
Adult: 25 mg once wkly for 16 wk. Maintenance: 15 mg wkly.

CrCl (ml/min)	Dosage Recommendation
61-80	75% of dose
51-60	70% of dose
10-50	30-50% of dose
<10	Avoid use

Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Special Populations: Monitor blood counts, renal and hepatic functions before, during and after each course.

Reconstitution: Reconstitute to 2.5-5 mg/ml with normal saline, D₅W, lactated Ringer's, or Elliott's B solution. Use preservative-free preparations.

Contraindications

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.

Warnings / 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.

Adverse Reactions

Ulceration of the mouth and GI disturbances (e.g. stomatitis and diarrhoea), bone marrow depression, hepatotoxicity, renal failure, skin reactions, alopecia, ocular irritation, arachnoiditis in intrathecal use, megaloblastic anaemia, osteoporosis, precipitation of diabetes, arthralgias, necrosis of soft tissue and bone, anaphylaxis, impaired fertility.
Potentially Fatal: Pulmonary reactions (e.g. interstitial lung disease); neurotoxicity (e.g. leukoencephalopathy, paresis, demyelination) with intrathecal use; foetal deaths.

Overdose Reactions

Nausea, vomiting, alopecia, melena, and renal failure.

Drug 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.
See Below for More methotrexate Drug Interactions

Food Interactions

May be given with meals to minimise GI discomfort. Serum levels may be decreased if taken with food. Decreased absorption in milk-rich food, decreased drug response with folate. Avoid ethanol (may be associated with increased liver injury). Avoid echinacea (has immunostimulant properties).

Mechanism of Actions

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.
Absorption: Rapidly absorbed from the GI tract at low doses, higher doses are less well absorbed. Rapidly and completely absorbed after IM doses. Peak plasma concentrations after 1-2 hr (oral), 30-60 min (IM).
Distribution: Tissues and extracellular fluids; crosses the blood-brain barrier and placenta; enters breast milk. Small amounts in saliva and breastmilk. 50% bound to plasma proteins. Bound as polyglutamate conjugates, bound drug may remain in the body for several mth, particularly in the liver .
Metabolism: Partly by intestinal flora. Does not undergo significant metabolism at low dose therapy; 7-hydroxy metabolite is detected at high-doses.
Excretion: Primarily via urine; small amounts in bile, faeces. Some evidence of enterohepatic recirculation. Interindividual variation exists, patients with delayed clearance are at an increased risk of toxicity.

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.)

Storage Conditions

Intramuscular: Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D₅W or normal saline are stable at room temperature (21-25°C) for 24 hr. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 mth, and up to 4 wk at room temperature. Intrathecal: Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D₅W or normal saline are stable at room temperature (21-25°C) for 24 hr. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 mth, and up to 4 wk at room temperature. Dilutions are stable for 7 days at room temperature, but are recommended to be used within 4-8 hr. Intravenous: Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D₅W or normal saline are stable at room temperature (21-25°C) for 24 hr. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 mth, and up to 4 wk at room temperature. Oral: Store tablets at room temperature (15-25°C). Protect from light. Parenteral: Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D₅W or normal saline are stable at room temperature (21-25°C) for 24 hr. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 mth, and up to 4 wk at room temperature.

ATC Classification

L01BA01 - methotrexate ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.
L04AX03 - methotrexate ; Belongs to the class of other immunosuppressive agents.