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Pronunciation |
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(meth
oh TREKS
ate) |

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U.S. Brand
Names |
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Folex® PFS;
Rheumatrex® |

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Generic
Available |
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Yes |

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Synonyms |
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Amethopterin; Methotrexate Sodium; MTX |

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Pharmacological Index |
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Antineoplastic Agent, Antimetabolite |

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

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Pregnancy Risk
Factor |
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D |

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Contraindications |
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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 |

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Warnings/Precautions |
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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). |

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Adverse
Reactions |
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>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
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Overdosage/Toxicology |
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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. |

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Drug
Interactions |
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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 |

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Stability |
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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
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Mechanism of
Action |
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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 |

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Pharmacodynamics/Kinetics |
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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 |

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Usual Dosage |
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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:
Clcr 61-80 mL/minute: Reduce dose to 75% of usual dose
Clcr 51-60 mL/minute: Reduce dose to 70% of usual dose
Clcr 10-50 mL/minute: Reduce dose to 30% to 50% of usual dose
Clcr <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 |

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Dietary
Considerations |
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Alcohol: Avoid use |

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Monitoring
Parameters |
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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 |

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Reference Range |
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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
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Mental Health: Effects
on Mental Status |
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May cause drowsiness or dizziness |

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Mental Health:
Effects on Psychiatric
Treatment |
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Leukopenia is common; avoid clozapine and carbamazepine |

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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |

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Dental Health:
Effects on Dental Treatment |
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Methotrexate commonly causes ulceration stomatitis, gingivitis, and
pharyngitis associated with oral discomfort |

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Patient
Information |
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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. |

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Nursing
Implications |
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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
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Dosage Forms |
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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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References |
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