Yes

Antineoplastic Agent, Antimetabolite

Treatment of trophoblastic neoplasms; leukemias; psoriasis; rheumatoid arthritis; breast, head and neck, and lung carcinomas; osteosarcoma; sarcomas; carcinoma of gastric, esophagus, testes; lymphomas

D

Hypersensitivity to methotrexate or any component; 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

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered

Because of the possibility of severe toxic reactions, fully inform patient of the risks involved. Do not use in women of childbearing age unless benefit outweighs risks; may cause hepatotoxicity, fibrosis, and cirrhosis, along with marked bone marrow depression. Death from intestinal perforation may occur. Risk of hepatotoxicity may be increased when administered with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine).

Patients should receive 1-2 L of I.V. fluid prior to initiation of high-dose methotrexate. Patients should receive sodium bicarbonate to alkalinize their urine during and after high-dose methotrexate (urine SG <1.010 and pH >7 should be maintained for at least 24 hours after infusion).

Toxicity to methotrexate or any immunosuppressive is increased in elderly; must monitor carefully. For rheumatoid arthritis and psoriasis, immunosuppressive therapy should only be used when disease is active and less toxic, traditional therapy is ineffective. Recommended doses should be reduced when initiating therapy in elderly due to possible decreased metabolism, reduced renal function, and presence of interacting diseases and drugs.

Methotrexate penetrates slowly into 3rd space fluids, such as pleural effusions or ascites, and exits slowly from these compartments (slower than from plasma).

>10%:

Central nervous system (with I.T. administration only):

Arachnoiditis: Acute reaction manifested as severe headache, nuchal rigidity, vomiting, and fever; may be alleviated by reducing the dose

Subacute toxicity: 10% of patients treated with 12-15 mg/m² of I.T. MTX may develop this in the second or third week of therapy; consists of motor paralysis of extremities, cranial nerve palsy, seizures, or coma. This has also been seen in pediatric cases receiving very high-dose I.V. MTX (when enough MTX can get across into the CSF).

Demyelinating encephalopathy: Seen months or years after receiving MTX; usually in association with cranial irradiation or other systemic chemotherapy

Dermatologic: Reddening of skin

Endocrine & metabolic: Hyperuricemia, defective oogenesis or spermatogenesis

Gastrointestinal: Ulcerative stomatitis, glossitis, gingivitis, nausea, vomiting, diarrhea, anorexia, intestinal perforation, mucositis (dose-dependent; appears in 3-7 days after therapy, resolving within 2 weeks)

Emetic potential:

<100 mg: Moderately low (10% to 30%)

greater than or equal to 100 mg or <250 mg: Moderate (30% to 60%)

greater than or equal to 250 mg: Moderately high (60% to 90%)

Hematologic: Leukopenia, thrombocytopenia

Renal: Renal failure, azotemia, nephropathy

Respiratory: Pharyngitis

1% to 10%:

Cardiovascular: Vasculitis

Central nervous system: Dizziness, malaise, encephalopathy, seizures, fever, chills

Dermatologic: Alopecia, rash, photosensitivity, depigmentation or hyperpigmentation of skin; painful plaque erosions have occurred in patients with psoriasis (frequency not determined)

Endocrine & metabolic: Diabetes

Genitourinary: Cystitis

Hematologic: Hemorrhage

Myelosuppressive: This is the primary dose-limiting factor (along with mucositis) of MTX; occurs about 5-7 days after MTX therapy, and should resolve within 2 weeks

WBC: Mild

Platelets: Moderate

Onset (days): 7

Nadir (days): 10

Recovery (days): 21

Hepatic: Hepatotoxic reactions, cirrhosis and portal fibrosis have been associated with chronic MTX therapy; acute elevation of liver enzymes are common after high-dose MTX, and usually resolve within 10 days

Neuromuscular & skeletal: Arthralgia

Ocular: Blurred vision

Renal: Renal dysfunction: Manifested by an abrupt rise in serum creatinine and BUN and a fall in urine output; more common with high-dose MTX, and may be due to precipitation of the drug. The best treatment is prevention: Aggressively hydrate with 3 L/m²/day starting 12 hours before therapy and continue for 24-36 hours; alkalinize the urine by adding 50 mEq of bicarbonate to each liter of fluid; keep urine flow >100 mL/hour and urine pH >7.

Respiratory: Pneumonitis: Associated with fever, cough, and interstitial pulmonary infiltrates; treatment is to withhold MTX during the acute reaction

Miscellaneous: Anaphylaxis, decreased resistance to infection

Symptoms of overdose include nausea, vomiting, alopecia, melena, renal failure

Antidote: Leucovorin; administer as soon as toxicity is seen; administer 10 mg/m² orally or parenterally; follow with 10 mg/m² orally every 6 hours for 72 hours. After 24 hours following methotrexate administration, if the serum creatinine is greater than or equal to 50% premethotrexate serum creatinine, increase leucovorin dose to 100 mg/m² every 3 hours until serum MTX level is <5 x 10^-8M. Hydration and alkalinization may be used to prevent precipitation of MTX or MTX metabolites in the renal tubules. Toxicity in low dose range is negligible, but may present mucositis and mild bone marrow suppression; severe bone marrow toxicity can result from overdose. Neither peritoneal nor hemodialysis have been shown to elimination. Leucovorin should be administered intravenously, never intrathecally, for over doses of intrathecal methotrexate.

Acute, intermittent hemodialysis with a high-flux hemodialyzer may be beneficial.

Decreased effect:

Corticosteroids: Reported to decrease uptake of MTX into leukemia cells. Administration of these drugs should be separated by 12 hours. Dexamethasone has been reported to not affect methotrexate influx into cells.

Decreases phenytoin, 5-FU

Increased toxicity:

Live virus vaccines vaccinia infections

Vincristine: Inhibits MTX efflux from the cell, leading to increased and prolonged MTX levels in the cell; the dose of VCR needed to produce this effect is not achieved clinically

Organic acids: Salicylates, sulfonamides, probenecid, and high doses of penicillins compete with MTX for transport and reduce renal tubular secretion. Salicylates and sulfonamides may also displace MTX from plasma proteins, MTX levels.

Ara-C: Increases formation of the Ara-C nucleotide can occur when MTX precedes Ara-C, thus promoting the action of Ara-C

Cyclosporine: CSA and MTX interfere with each others renal elimination, which may result in increased toxicity

Nonsteroidal anti-inflammatory drugs (NSAIDs): Should not be used during moderate or high-dose methotrexate due to increased and prolonged methotrexate levels may increase toxicity

Hepatotoxic agents (azathioprine, retinoids, sulfasalazine) may increase the risk of hepatotoxic reactions

Store intact vials at room temperature (15°C to 25°C) and protect from light

Use preservative-free preparations for high-dose and intrathecal administration

Dilute powder with D₅W or NS to a concentration of less than or equal to 25 mg/mL (20 mg and 50 mg vials) and 50 mg/mL (1 g vial) as follows; solution is stable for 7 days at room temperature

20 mg = 20 mL (1 mg/mL)

50 mg = 5 mL (10 mg/mL)

1 g = 19.4 mL (50 mg/mL)

Further dilution in D₅W or NS is stable for 24 hours at room temperature (21°C to 25°C)

Standard I.V. dilution:

Maximum syringe size for IVP is a 30 mL syringe and syringe should be less than or equal to 75% full

Doses <149 mg: Administer slow I.V. push

Dose/syringe (concentration less than or equal to 25 mg/mL)

Doses of 150-499 mg: Administer IVPB over 20-30 minutes

Dose/50 mL D₅W or NS

Doses of 500-1500 mg: Administer IVPB over greater than or equal to 60 minutes

Dose/250 mL D₅W or NS

Doses of >1500 mg: Administer IVPB over 1-6 hours

Dose/1000 mL D₅W or NS

Standard I.M. dilution: Dose/syringe (concentration = 25 mg/mL)

I.V. dilutions are stable for 8 days at room temperature (25°C)

Intrathecal solutions in 3-20 mL LR are stable for 7 days at room temperature (30°C); compatible with cytarabine and hydrocortisone in LR or NS for 7 days at room temperature (25°C)

Standard intrathecal dilution: Dose/3-5 mL LR +/- methotrexate (12 mg) +/- hydrocortisone (15-25 mg)

Intrathecal dilutions are stable for 7 days at room temperature (25°C) but due to sterility issues, use within 24 hours

An antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells

Folates are activated by dihydrofolate reductase (DHFR)

DHFR is inhibited by MTX (by binding irreversibly), causing an increase in the intracellular dihydrofolate pool (the inactive cofactor) and inhibition of both purine and thymidylate synthesis (TS)

MTX enters the cell through an energy-dependent and temperature-dependent process which is mediated by an intramembrane protein; this carrier mechanism is also used by naturally occurring reduced folates, including folinic acid (leucovorin), making this a competitive process

At high drug concentrations (>20 mM), MTX enters the cell by a second mechanism which is not shared by reduced folates; the process may be passive diffusion or a specific, saturable process, and provides a rationale for high-dose MTX

A small fraction of MTX is converted intracellularly to polyglutamates, which leads to a prolonged inhibition of DHFR

The MOA in the treatment of rheumatoid arthritis is unknown, but may affect immune function

In psoriasis, methotrexate is thought to target rapidly proliferating epithelial cells in the skin

Onset of effect: Antirheumatic effects may require several weeks

Absorption:

Oral: Rapid; well absorbed orally at low doses (<30 mg/m²), incomplete absorption after large doses

I.M. injection: Completely absorbed

Distribution: Drug penetrates slowly into 3rd space fluids, such as pleural effusions or ascites, and exits slowly from these compartments (slower than from plasma); crosses the placenta with small amounts appearing in breast milk; does not achieve therapeutic concentrations in the CSF and must be given intrathecally if given for CNS prophylaxis or treatment; sustained concentrations are retained in the kidney and liver

Protein binding: 50%

Metabolism: <10% metabolized; degraded by intestinal flora to DAMPA by carboxypeptidase; aldehyde oxidase in the liver converts MTX to 7-OH MTX; polyglutamates are produced intracellularly and are just as potent as MTX; their production is dose and duration dependent and are slowly eliminated by the cell once they are formed

Half-life: 8-12 hours with high doses and 3-10 hours with low doses

Time to peak serum concentration: Oral: 1-2 hours; Parenteral: 30-60 minutes

Elimination: Small amounts excreted in the feces; primarily excreted in the urine (44% to 100%) via glomerular filtration and active transport

Miscellaneous: Cytotoxicity is determined by both drug concentration and duration of cell exposure; extracellular drug concentrations of 1 x 10^-8M are required to inhibit thymidylate synthesis; reduced folates are able to rescue cells and reverse MTX toxicity if given within 48 hours of the MTX dose; at concentrations of >10 mM MTX, reduced folates are no longer effective

Refer to individual protocols. May be administered orally, I.M., intra-arterially, intrathecally, or I.V.

Children:

Dermatomyositis: Oral: 15-20 mg/m²/week as a single dose once weekly or 0.3-1 mg/kg/dose once weekly

Juvenile rheumatoid arthritis: Oral, I.M.: 5-15 mg/m²/week as a single dose or as 3 divided doses given 12 hours apart

Antineoplastic dosage range:

Oral, I.M.: 7.5-30 mg/m²/week or every 2 weeks

I.V.: 10-18,000 mg/m² bolus dosing or continuous infusion over 6-42 hours

Dosing schedules listed below:

Conventional Dose:

15-20 mg/m² oral twice weekly

30-50 mg/m² oral, I.V. weekly

15 mg/day for 5 days oral, I.M. every 2-3 weeks

Intermediate Dose:

50-150 mg/m² I.V. push every 2-3 weeks

240 mg/m²* I.V. infusion every 4-7 days

0.5-1 g/m²* I.V. infusion every 2-3 weeks

High Dose:

1-12 g/m²* I.V. infusion every 1-3 weeks

*Followed with leucovorin rescue - refer to leucovorin monograph for details.

Pediatric solid tumors (high-dose): I.V.:

<12 years: 12 g/m² (dosage range: 12-18 g)

greater than or equal to 12 years: 8 g/m² (maximum: 18 g)

Acute lymphocytic leukemia (intermediate-dose): I.V.: Loading: 100 mg/m² over 1 hour, followed by a 35-hour infusion of 900 mg/m²/day

Meningeal leukemia: I.T.: 10-15 mg/m² (maximum dose: 15 mg) or

less than or equal to 3 months: 3 mg/dose

4-11 months: 6 mg/dose

1 year: 8 mg/dose

2 years: 10 mg/dose

greater than or equal to 3 years: 12 mg/dose

I.T. doses are prepared with preservative-free MTX only. Hydrocortisone may be added to the I.T. preparation; total volume should range from 3-6 mL. Doses should be repeated at 2- to 5-day intervals until CSF counts return to normal followed by a dose once weekly for 2 weeks then monthly thereafter.

Adults: I.V.: Range is wide from 30-40 mg/m²/week to 100-12,000 mg/m² with leucovorin rescue

Doses not requiring leucovorin rescue range from 30-40 mg/m² I.V. or I.M. repeated weekly, or oral regimens of 10 mg/m² twice weekly

High-dose MTX is considered to be >100 mg/m² and can be as high as 1500-7500 mg/m². These doses require leucovorin rescue. Patients receiving doses greater than or equal to 1000 mg/m² should have their urine alkalinized with bicarbonate or Bicitra® prior to and following MTX therapy.

Trophoblastic neoplasms: Oral, I.M.: 15-30 mg/day for 5 days; repeat in 7 days for 3-5 courses

Head and neck cancer: Oral, I.M., I.V.: 25-50 mg/m² once weekly

Rheumatoid arthritis: Oral: 7.5 mg once weekly OR 2.5 mg every 12 hours for 3 doses/week; not to exceed 20 mg/week

Psoriasis: Oral: 2.5-5 mg/dose every 12 hours for 3 doses given weekly or Oral, I.M.: 10-25 mg/dose given once weekly

Ectopic pregnancy: I.M./I.V.: 50 mg/m² single-dose without leucovorin rescue

Elderly: Rheumatoid arthritis/psoriasis: Oral: Initial: 5 mg once weekly; if nausea occurs, split dose to 2.5 mg every 12 hours for the day of administration; dose may be increased to 7.5 mg/week based on response, not to exceed 20 mg/week

Dosing adjustment in renal impairment:

Cl_cr 61-80 mL/minute: Reduce dose to 75% of usual dose

Cl_cr 51-60 mL/minute: Reduce dose to 70% of usual dose

Cl_cr 10-50 mL/minute: Reduce dose to 30% to 50% of usual dose

Cl_cr <10 mL/minute: Avoid use

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

Dosage adjustment in hepatic impairment:

Bilirubin 3.1-5 mg/dL OR AST >180 units: Administer 75% of usual dose

Bilirubin >5 mg/dL: Do not use

Alcohol: Avoid use

For prolonged use (especially rheumatoid arthritis, psoriasis) a baseline liver biopsy, repeated at each 1-1.5 g cumulative dose interval, should be performed; WBC and platelet counts every 4 weeks; CBC and creatinine, LFTs every 3-4 months; chest x-ray

Refer to chart in Leucovorin Calcium monograph. Therapeutic levels: Variable; Toxic concentration: Variable; therapeutic range is dependent upon therapeutic approach.

10^-6 Molar unit = 1 microMolar unit

Toxic: Low-dose therapy: >9.1 ng/mL; high-dose therapy: >454 ng/mL

May cause drowsiness or dizziness

Leukopenia is common; avoid clozapine and carbamazepine

No information available to require special precautions

Methotrexate commonly causes ulceration stomatitis, gingivitis, and pharyngitis associated with oral discomfort

Avoid alcohol to prevent serious side effects. Avoid intake of extra dietary folic acid, maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) and adequate nutrition (frequent small meals may help). You may experience nausea and vomiting (small frequent meals may help or request antiemetic from prescriber); drowsiness, tingling, numbness, or blurred vision (avoid driving or engaging in tasks that require alertness until response to drug is known); mouth sores (frequent oral care is necessary); loss of hair; permanent sterility; skin rash; photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report black or tarry stools, fever, chills, unusual bleeding or bruising, shortness of breath or difficulty breathing, yellowing of skin or eyes, dark or bloody urine, or acute joint pain or other side effects you may experience. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. The drug may cause permanent sterility and may cause birth defects. Do not breast-feed.

For intrathecal use, mix methotrexate without preservatives with normal saline or lactated Ringer's to a concentration no greater than 2 mg/mL; can be administered I.V. push, I.V. intermittent infusion, or I.V. continuous infusion at a concentration <25 mg/mL; doses >100-300 mg/m² are usually administered by I.V. continuous infusion and are followed by a course of leucovorin rescue

Monitor CBC with differential and platelet count, creatinine clearance, serum creatinine, BUN, and hepatic function tests, LFTs every 3-4 months, chest x-ray; for prolonged use (especially rheumatoid arthritis, psoriasis) a baseline liver biopsy, repeated at each 1-1.5 g cumulative dose interval, should be performed

Injection, as sodium: 2.5 mg/mL (2 mL); 25 mg/mL (2 mL, 4 mL, 8 mL, 10 mL)

Injection, as sodium, preservative free: 25 mg (2 mL, 4 mL, 8 mL, 10 mL)

Powder, for injection: 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 1 g

Tablet, as sodium: 2.5 mg

Tablet, as sodium, dose pack: 2.5 mg (4 cards with 2, 3, 4, 5, or 6 tablets each)

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