Methotrexate

DRUG NAME: Methotrexate

SYNONYM(S): amethopterin,1 MTX

COMMON TRADE NAME(S):

CLASSIFICATION: antimetabolite

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Methotrexate is a folate antagonist.2 Tetrahydrofolate is the active form of folic acid required for purine and
thymidylate synthesis. Folic acid is reduced to tetrahydrofolate by dihydrofolate reductase (DHFR). The cytotoxicity
of methotrexate results from three actions: inhibition of DHFR, inhibition of thymidylate, and alteration of the
transport of reduced folates.3 Inhibition of DHFR results in a deficiency of thymidylate and purines and therefore a
decrease in DNA synthesis, repair and cellular replication.3 The affinity of DHFR to methotrexate is far greater than
its affinity for folic acid or dihydrofolic acid, therefore large doses of folic acid given simultaneously will not reverse
the effects of methotrexate.2 However, leucovorin calcium, a derivative of tetrahydrofolic acid, may block the effects
of methotrexate if given shortly after the methotrexate since it does not require DHFR for activation.2
Moderate (> 100 mg/m2) to high-dose methotrexate (> 1000 mg/m2)4 plus leucovorin rescue is routinely used
therapeutically in cancer treatment.3 Methotrexate is most active against rapidly multiplying cells because the
cytotoxic effects occur primarily during the S phase of the cell cycle.3 Methotrexate also has immunosuppressive
activity, possibly due to inhibition of lymphocyte multiplication.5

PHARMACOKINETICS:
Interpatient variability significant differences in time to peak concentration
Oral Absorption highly variable and dose dependent5; 60% for doses up to 30 mg/m2; significantly less for
doses >80mg/m2
food delays absorption and reduces peak concentration
time to peak plasma 1-2 h
concentration
Distribution actively transported across cell membranes at serum concentrations < 0.1 µmol/mL, mainly
passive diffusion at higher concentration5; widely distributed with highest concentration in
kidneys, gallbladder, spleen, liver, and skin5; also distributes into third space fluids5
cross blood brain barrier? a ratio of 10-30:1 for CNS concentrations of
methotrexate6; higher CNS concentrations noted in
patients with recent cranial irradiation and in patients
with primary CNS lymphoma due to disruption of the
blood-brain barrier
volume of distribution 0.4-0.8 L/kg
plasma protein binding 50%
Metabolism <10%; hepatic and intracellular
active metabolite methotrexate polyglutamates5 and 7-hydroxy-
methotrexate7
inactive metabolite 4-amino-4-deoxy-N10-methylpteroic acid (DAMPA)8
Excretion primarily renal via glomerular filtration and active tubular secretion
urine 80-90%

BC Cancer Drug Manual© Page 1 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

feces 10% biliary

terminal half life 3-10 h for doses < 30 mg/m2; 8-15 h for higher doses5
clearance decreased at higher doses
Children8 more rapid elimination in urine; greater volume of distribution
Adapted from standard reference2 unless specified otherwise.

USES:
Primary uses: Other uses:
*Bladder cancer Leukemia, acute lymphocytic9
*Breast cancer Leukemia, acute promyelocytic9
*Gastric cancer Sarcoma, soft tissue9
*Choriocarcinoma Lymphoma, intraocular10
Gestational trophoblastic cancer11
*Head and neck cancer
*Leptomeningeal cancer
*Leukemia, acute lymphoblastic
*Lymphoma, Burkitt’s
*Lymphoma, childhood
*Lymphoma, cutaneous T-cell (mycosis fungoides)
*Lymphoma, non-Hodgkin’s
*Sarcoma, osteogenic
Urothelial cancer12
*Health Canada approved indication

SPECIAL PRECAUTIONS:

Caution:
• Pleural effusions or ascites3: Methotrexate exits slowly from third space compartments resulting in prolonged
half-life and unexpected toxicity. In patients with significant third space accumulation, the fluid should be removed
prior to treatment and methotrexate levels should be monitored.3 If the fluid cannot be drained prior to therapy, a
dose reduction is appropriate.13

Special populations: Elderly patients may be at increased risk for toxicity due to decreased hepatic and renal
function, as well as decreased folate stores.3 A dose reduction as well as monitoring for early signs of toxicities
should be considered.3

Carcinogenicity: There are no controlled studies in humans. Evidence regarding increased risk of tumours is
conflicting, complicating the assessment of carcinogenic potential. Malignant lymphomas have been reported in
patients receiving low-dose methotrexate, but in some patients, they may regress without treatment following
methotrexate withdrawal. Animal studies have been inconclusive. However, there is evidence that methotrexate
causes chromosomal damage to animal somatic cells and human bone marrow cells; clinical significance is
unknown.14

Mutagenicity: Clastogenic in mammalian in vitro and in vivo chromosome tests.5

Fertility: Methotrexate therapy may result in impairment of fertility, oligospermia, and menstrual dysfunction in
humans, during and for a short period after cessation of therapy.14,15

Pregnancy: Methotrexate can cause fetal death, embryotoxicity, abortion, and teratogenic effects in humans. The
optimal time interval between cessation of methotrexate treatment of either partner and pregnancy has not been
established. Published intervals vary from 3 months to 1 year after treatment has ended.14,15
BC Cancer Drug Manual© Page 2 of 17 Methotrexate
This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

Breastfeeding is contraindicated as methotrexate has been detected in human breast milk.14,15

Leucovorin rescue4 is required in some methotrexate regimens.

Methotrexate dose:
 >500 mg/m2 requires leucovorin rescue.
 100-500 mg/m2 may require leucovorin rescue.

Bleyer Nomogram:

Reference: Bleyer WA. The clinical pharmacology of methotrexate – new applications of an old drug. Cancer 1978:41(1):36-51

Note: 0.05 micromol/L = 5 x 10-2 micromoles/L

Leucovorin dose PO/IV/IM (see Bleyer nomogram):

• 10-25 mg/m2 every 6 hours for approximately 8 to 10 doses, starting 24 hours after the start of methotrexate
infusion.4,16-20 (note: for leucovorin doses >25 mg administer IV).21
• Leucovorin dose modifications begin on day 3, if required, based on methotrexate levels taken that morning (i.e.,
level taken 36-48 hours following the start of the methotrexate infusion). Methotrexate levels are repeated every
morning and leucovorin adjusted based on the graph to follow.16-18
• Continue until the methotrexate level is <0.05 to 0.1 micromol/L.22,23 The change in threshold concentration from
0.05 microl/L (as per Bleyer nomogram) to 0.1 micromol/L is a result of worldwide changes in the immunoassay
used to measure methotrexate serum levels. New laboratory methods have a higher limit of detection than
previous methods and inaccuracies have been reported with methotrexate levels below 0.1 micromol/L.24

Note: Leucovorin doses >25 mg should be given IV21

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal
relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event
rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they

BC Cancer Drug Manual© Page 3 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be
clinically important.25 When placebo-controlled trials are available, adverse events are included if the incidence is >
5% higher in the treatment group.

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

allergy/immunology anaphylaxis (<1%)

vasculitis (1-10%)
auditory/hearing tinnitus
blood/bone marrow/ anemia
febrile neutropenia
neutropenia: 1st nadir 4-7 days with recovery in 7-13 days; 2nd nadir 12-21 days with
recovery in 15-20 days26
thrombocytopenia: nadir 5-12 days with recovery in 15-27 days26
cardiovascular (general) hypotension
pericardial effusion
pericarditis
constitutional symptoms chills and fever (frequent)26
fatigue (frequent)26
malaise (1-10%)
mood alteration; with low-dose methotrexate
dermatology/skin extravasation hazard: none27
acne
alopecia (1-10%); usually reversible but may require several months26
dermatitis
erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, toxic
epidermis necrolysis3
folliculitis
furunculosis
photosensitivity (1-10%)
pigmentary changes (1-10%)
pruritus
rash (1-10%); on extremities26
reddening of skin (>10%)
skin necrosis3
telangiectasia
urticaria
endocrine diabetes (1-10%)
gastrointestinal emetogenic potential28: dose-related: moderate (high-moderate for >1000 mg/m2; low-
moderate for 250-1000 mg/m2); low for <250 mg/m2 to >50 mg/m2; rare for <50 mg/m2
abdominal discomfort

BC Cancer Drug Manual© Page 4 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

anorexia (>10%)
diarrhea (>10%)
gingivitis (>10%)
glossitis (>10%)
nausea; dose-related
perforation (>10%)4
pharyngitis
stomatitis (>10%)
vomiting; dose-related
hemorrhage ecchymoses, petechiae
hematemesis5
hematuria
melena5
hepatobiliary/pancreas pancreatitis
hepatic hepatoxicity (1-10%)
metabolic/laboratory azotemia; more common with high-dose methotrexate than with low-dose25
hyperuricemia (>10%)
liver function tests, elevated5; usually transient, asymptomatic and return to normal
within 10 to 14 days25
musculoskeletal arthralgia/myalgia (1-10%)
hemiparesis
osteoporosis, fractures; with high-dose methotrexate26
osteonecrosis
soft tissue necrosis
neurology neurotoxicities (>10%); with intrathecal administration or high-dose methotrexate
cognitive dysfunction, mild transient (<1%); with low-dose methotrexate26
cranial sensations; with low-dose methotrexate
dizziness (1-10%)
seizure (1-10%)
ocular/visual blurred vision (1-10%)
conjunctivitis
eye discomfort
severe visual changes
pain headache26

BC Cancer Drug Manual© Page 5 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

ORGAN SITE SIDE EFFECT

Clinically important side effects are in bold, italics

pulmonary pulmonary toxicity (2-8%)29; can occur with all doses of methotrexate, although more
often with chronic low-dose25
renal/genitourinary renal dysfunction (1-10%); with high-dose methotrexate
secondary malignancy lymphomas; may regress following withdrawal of methotrexate3
sexual/reproductive abortifacient, fetal defects26
function
gynecomastia
loss of libido/impotence
menstrual dysfunction
oogenesis, interference with
spermatogenesis, interference with
vaginal discharge
syndromes acute neurologic syndrome (<1%); with high-dose methotrexate
tumour lysis syndrome; especially when given for systemic Burkitt’s lymphoma25
vascular cerebral thrombosis
deep vein thrombosis
pulmonary embolism
retinal vein thrombosis

Adapted from standard references2,30 unless specified otherwise.

Glucarpidase (carboxypeptidase-G2, CPDG2, VORAXAZE®31,32) is a recombinant bacterial enzyme that inactivates

extracellular methotrexate to 2,4-diamino-N10–methylpteroic acid [DAMPA].31 Glucarpidase can rapidly lower serum
methotrexate levels by >95% within 15 minutes of administration.33 Cellular uptake of glucarpidase is increased
when it is given with leucovorin. However, leucovorin is a weak substrate for glucarpidase and may compete with
methotrexate for binding. Therefore, administration time of leucovorin and glucarpidase should be separated.31 Also,
leucovorin should be continued after administration of glucarpidase, which may deactivate the active metabolite of
leucovorin34,35. Glucarpidase can be used to treat patients at risk for methotrexate toxicity secondary to delayed
elimination31 and is available through the Health Canada Special Access Programme:
• Glucarpidase 50 units/kg IV over 5 minutes31
o For methotrexate level >100 micromol/L, may give second dose of glucarpidase 48 hours after administration
of first dose.36
• High-dose leucovorin (eg, 1000 mg/m2 IV every 6 hours) should be given prior to the receipt and administration of
glucarpidase.36
o Leucovorin should be given at least 2-4 hours before or after administration of glucarpidase.31
o After administration of glucarpidase, leucovorin should be continued at a high dose of 250 mg/m2 IV every 6
hours for a total of 48 hours; after that time, leucovorin rescue should be modified based on methotrexate
levels and clinical signs of toxicity.36
o Note that following glucarpidase administration, methotrexate level based on standard clinical immunoassay
methods may be artificially high due to interference from high levels of DAMPA.31

Methotrexate-induced hepatotoxicity can be seen with both high and low-dose methotrexate, and can be life-
threatening.26 Increased serum aminotransferases (14%) and less commonly hyperbilirubinemia is seen more often
in high-dose methotrexate.8 The liver enzymes can increase with each cycle, and usually return to pre-treatment
levels once methotrexate has been discontinued for 1 month.37 Cirrhosis and fibrosis are more often seen with
BC Cancer Drug Manual© Page 6 of 17 Methotrexate
This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

chronic low-dose methotrexate.8,37 See Dosing guidelines for hepatic failure. Patients should be warned to avoid
alcohol, prescription medications or herbal supplements that may increase risk of hepatotoxicity.25

Hyperuricemia may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or
acute renal failure.38 It is most likely with highly proliferative tumours of massive burden, such as leukemias, high-
grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with pre-existing renal
dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients39:
• aggressive hydration: 3 L/m²/24 hr with target urine output >100 ml/h
• if possible, discontinue drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates)
• monitor electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hours
• replace electrolytes as required
• allopurinol 600 mg po initially, then 300 mg po q6h x6 doses, then 300 mg po daily x 5-7 days
Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to
maintain urine pH greater than 7. Rasburicase (FASTURTEC®) is a novel uricolytic agent that catalyzes the
oxidation of uric acid to a water-soluble metabolite, removing the need for alkalinization of the urine.40 It may be
used for treatment or prophylaxis of hyperuricemia; however, its place in therapy has not yet been established.
Aluminum hydroxide (e.g., AMPHOGEL®) may be added orally if phosphate becomes elevated. If aluminium
hydroxide has been added, discontinue sodium bicarbonate.41

Neurologic complications30: Methotrexate-induced neurotoxicities can be seen with intrathecal injection of

methotrexate and with high-dose methotrexate.4 The neurotoxicities may be due to the accumulation of adenosine
resulting from the inhibition of purine synthesis.26

For Intrathecal (IT) administration

• Aseptic meningitis30: This is the most common toxicity seen with IT administration (10%); includes headache,
neck rigidity, back pain, nausea, vomiting, fever, and lethargy. Aseptic meningitis can begin 2-4 hours after the
drug is injected, and can last 12-72 hours. There is usually no treatment required; the risk of developing this can
be decreased by the administration of IT hydrocortisone, or oral corticosteroids. Patients may be rechallenged.
• Transverse myelopathy30: This is much less common30; includes isolated spinal cord dysfunction over hours or
days. Transverse myelopathy can begin between 30 minutes and 48 hours after treatment. This is more common
with concurrent radiotherapy or frequent IT injections of methotrexate. Recovery from this condition is variable.
Patients are not rechallenged.
• Leukoencephalopathy30: This can be a delayed complication and is more common in patients receiving whole
brain radiotherapy or previous IV methotrexate. Symptoms include confusion, irritability, somnolence, ataxia,
dementia, and occasionally seizures and coma.5
• Encephalopathy, seizures, neurologic deficits, lumbosacral radiculopathy, neurogenic pulmonary edema, and
sudden death can rarely occur.30

For high-dose methotrexate (>1000 mg/m2)

• Acute neurotoxicity30: includes somnolence, confusion, and seizures within 24 hours of treatment. These usually
resolve spontaneously; rechallenge is possible.
• Subacute neurotoxicity30: seen with weekly or every two week administration. “Stroke-like” syndrome, including
transient neurologic deficits, confusion, and seizures. Occurring about 6 days after drug administration, lasting
from 15 minutes to 72 hours and then resolving. Rechallenge is possible.
Leukoencephalopathy: refer to “for IT administration” above.

Methotrexate-induced pulmonary toxicity can be seen with both high and low-dose methotrexate, and can be life-
threatening.26 Pulmonary toxicity can be either symptomatic or asymptomatic and can be caused by inflammation,
infection or neoplasia.26
• Inflammatory lung disease: most common here is hypersensitivity pneumonitis.29
• Pulmonary infections: opportunistic infections due to compromised immune system.29
• Pulmonary lymphoma: Non-Hodgkin’s (B cell) lymphoma which regresses after discontinuation of methotrexate.29
Methotrexate-induced pulmonary toxicity can be acute, subacute, or chronic.29 Patients who experience pulmonary
toxicity will often develop this within the first year of methotrexate therapy, but it can occur much earlier or much
later.29 Subacute toxicity is the most common and includes dyspnea, non-productive cough, fever, crackles,
cyanosis, pulmonary fibrosis, pleural effusions.29 Treatment includes discontinuing methotrexate and initiating
BC Cancer Drug Manual© Page 7 of 17 Methotrexate
This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

corticosteroid therapy.29 Improvement can occur within days of stopping methotrexate; rechallenging with the drug is
not recommended.29

High-dose methotrexate-induced renal failure is a medical emergency because methotrexate is mainly eliminated
by the kidneys.42 Renal damage is due to precipitation of methotrexate in the tubules and to tubule injury. Drug
precipitation can often be prevented by hydration and alkalization of the urine.8 Hydration produces a high urine
output and lowers the concentration of methotrexate in the tubular fluid; alkalization of the urine increases the
solubility of methotrexate. During the recovery period sustained methotrexate levels may result in substantial bone
marrow and gastrointestinal toxicity.25 Management should include continued monitoring of methotrexate levels,
administration of leucovorin (see leucovorin rescue) and alkalinized intravenous fluids until plasma levels fall below
0.05 micromol/L.25

INTERACTIONS:
AGENT EFFECT MECHANISM MANAGEMENT
acitretin4,43 delayed, major, suspected; unknown avoid concurrent use
increased methotrexate
hepatic toxicity
alcohol4 enhanced hepatotoxicity additive limit or avoid alcohol
intake during therapy
aminoglycosides, oral43 delayed, moderate, decreased GI absorption consider parenteral use of
possible; decreased of methotrexate methotrexate
methotrexate levels
amiodarone43 delayed, major, possible; unknown consider monitoring for
increased methotrexate methotrexate toxicity
levels
asparaginase44 decreased effect of suppression of asparagine give asparaginase 9-10
methotrexate when concentrations days before methotrexate
asparaginase is given or shortly after
immediately prior to or with methotrexate
methotrexate; enhanced
effect of methotrexate
when asparaginase is
given after methotrexate
azathioprine43 delayed, moderate, decreased metabolism of primarily a concern with
possible; increased azathioprine high-dose methotrexate;
azathioprine levels dose reduction may be
considered for
azathioprine
bile acid sequestrants may decrease decreased absorption of separate the
(e.g., cholestyramine, methotrexate levels methotrexate45 administration of these
colestipol)45 drugs by 2 or more hours
caffeine43 delayed, moderate, unknown monitor clinical response;
possible; decreased consider reduction in
methotrexate caffeine intake if needed
antirheumatic effect
carboxypeptidase G2 decreased toxicity of rapidly metabolizes may be used to rapidly
(CPDG2)46 methotrexate methotrexate lower serum methotrexate
chloroquine43 delayed, minor, possible; unknown monitor clinical response;
decreased methotrexate consider increase in
antirheumatic effect methotrexate dose

BC Cancer Drug Manual© Page 8 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

AGENT EFFECT MECHANISM MANAGEMENT

corticosteroids4 may decrease may decrease the uptake separate the
methotrexate levels in of methotrexate into administration of these
leukemia cells leukemia cells drugs by 12 hours; note
that dexamethasone does
not appear to affect
methotrexate uptake into
cells
cyclosporine4 may increase both unknown47 monitor for both
methotrexate and cyclosporine and
cyclosporine toxicity methotrexate toxicity47
cytarabine4 methotrexate, when unknown some protocols are
administered prior to designed to take
cytarabine, may enhance advantage of this effect;
the efficacy and toxicity of monitor toxicity
cytarabine
digoxin43 delayed, moderate, decreased GI absorption monitor for digoxin
suspected; decreased of digoxin pharmacologic effects
digoxin levels
doxycycline43 delayed, major, possible; unknown monitor for methotrexate
increased methotrexate toxicity
levels
haloperidol43 delayed, moderate, unknown monitor for methotrexate
possible; increased toxicity
methotrexate
dermatological toxicity
hydroxychloroquine43 delayed, minor, possible; unknown monitor clinical response;
decreased methotrexate consider increase in
antirheumatic effect methotrexate dose
leucovorin decreased toxicity of leucovorin “rescues” administer leucovorin
methotrexate normal cells from toxic after methotrexate if
effects of methotrexate required
mercaptopurine4,43 delayed, moderate, decreased metabolism of primarily a concern with
possible; increased mercaptopurine high-dose methotrexate;
mercaptopurine levels dose reduction may be
considered for
mercaptopurine
NSAIDs (e.g., diclofenac, delayed, major, suspected; reduced renal clearance of primarily a concern with
ibuprofen, naproxen)4,43 increased methotrexate methotrexate high-dose methotrexate;
levels monitor methotrexate
levels i.e., longer
leucovorin rescue; note
that risk may be lower with
selective COX-2 inhibitors
(e.g., celecoxib)
omeprazole, pantoprazole, increased methotrexate mechanism unclear; monitor for methotrexate
esomeprazole, other and 7-hydroxy- possibly reduced renal toxicity; for high-dose
proton pump inhibitors methotrexate levels, clearance of methotrexate methotrexate, consider
(PPI)7,48-51 leading to increased and 7-hydroxy- discontinuing PPI one day
methotrexate toxicity methotrexate prior to methotrexate;
consider an H2 antagonist
(e.g., ranitidine) instead of
PPI

BC Cancer Drug Manual© Page 9 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

AGENT EFFECT MECHANISM MANAGEMENT

penicillins (e.g., delayed, major, suspected; competitive inhibition of primarily a concern with
amoxicillin, piperacillin, increased methotrexate renal tubular secretion of high doses of penicillins
ticarcillin)4,43 levels methotrexate and high-dose
methotrexate; monitor for
methotrexate toxicity
longer leucovorin rescue
phenytoin43 delayed, moderate, decreased absorption or monitor for phenytoin
suspected; decrease increased metabolism of levels
phenytoin levels phenytoin
probenecid4,43 rapid, major, probable; decreased renal excretion primarily a concern with
increased methotrexate of methotrexate. high-dose methotrexate;
levels monitor methotrexate
levels i.e., longer
leucovorin rescue
procarbazine43 delayed, major, possible; unknown consider allowing an
increased methotrexate interval of > 72 h between
renal toxicity the administration of the
final dose of procarbazine
and the initiation of a high-
dose methotrexate
infusion
salicylates (e.g., rapid, major, suspected; decreased renal clearance salicylate doses used for
ASA)4,43,52,53 increased methotrexate and plasma protein prophylaxis of
levels binding of methotrexate cardiovascular events are
not likely to be a concern;
consider monitoring
methotrexate levels
sulfonamides (e.g., co- delayed, major, suspected; decreased protein binding primarily a concern with
trimoxazole, increased methotrexate and renal clearance of high-dose methotrexate;
sulfamethoxazole, levels methotrexate; monitor methotrexate
sulfisoxazole)4,43,52,53 methotrexate may induce levels i.e., longer
folate deficiency, which leucovorin rescue
can develop into acute
megaloblastic anemia
upon administration of
timethoprin-
sulfamethoxazole
tetracycline43 delayed, major, possible; unknown monitor for methotrexate
increased methotrexate toxicity
levels
theophylline4 methotrexate may decreased clearance of monitor for theophylline
increase theophylline theophylline5 levels5
levels
thiazides43 delayed, moderate, unknown consider alternative
possible; increased antihypertensive therapy
methotrexate induced
myelosuppression
trimethoprim43 delayed, major, suspected; both drugs are folate monitor for methotrexate
increased methotrexate antagonists and may have toxicity
toxicities synergistic effect on folate
metabolism

BC Cancer Drug Manual© Page 10 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

AGENT EFFECT MECHANISM MANAGEMENT

urine alkalizers (e.g., rapid, minor, possible; increased renal excretion no clinical intervention
potassium acetate, decreased methotrexate of methotrexate required
potassium citrate, sodium levels
acetate, sodium
bicarbonate, sodium
citrate, sodium lactate)

SUPPLY AND STORAGE:

Oral:
Accord Healthcare Inc.,54 Apotex Inc.,55 and Pharmascience Inc.56 supplies methotrexate as 2.5 mg tablets. Tablets
contain lactose. Store at room temperature and protect from light.

Pfizer Canada ULC supplies methotrexate as 10 mg tablets. Tablets contain lactose. Store at room temperature and
protect from light.57

Injection:
Pfizer Canada ULC supplies methotrexate as 20 mg/2 mL and 50 mg/2 mL ready-to-use, single use (preservative
free) vials; as 500 mg/20 mL, 1 g/40 mL, and 2.5 g/100 mL ready-to-use, multi-dose (preservative free) vials; and as
50 mg/2 mL and 500 mg/20 mL ready-to-use, multi-dose (with preservative) vials. Store at room temperature.
Protect from light.14

Accord Healthcare Inc. supplies methotrexate as 50 mg/2 mL, 500 mg/20 mL, and 1 g/40 mL ready-to-use, single
use (preservative free) vials and 50 mg/2 mL and 500 mg/20 mL ready-to-use, multi-dose (with preservative) vials.
Store at room temperature. Protect from light.15

For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability
Chart in Appendix.

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on the current brand used at BC Cancer, see Chemotherapy Preparation and Stability
Chart in Appendix.

Additional information:
• methotrexate is sparingly soluble in acidic conditions and precipitation may occur2
• for intraocular use (i.e., intravitreal injection), preservative free methotrexate is preferred58

Compatibility: consult detailed reference

PARENTERAL ADMINISTRATION:
BC Cancer administration guideline noted in bold, italics
Subcutaneous can be used8
Intramuscular inject into a suitable muscle11,14,59,60
Direct intravenous IV push48,61
Intermittent infusion* over 20 min to 24 h30
Continuous infusion* over 24-42 h30
Intraperitoneal no information found

BC Cancer Drug Manual© Page 11 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

BC Cancer administration guideline noted in bold, italics

Intrapleural no information found
Intrathecal† dilute in small volume (5-10 mL)62 preservative-free
NS to a concentration of 1-2 mg/mL5,63; some
clinicians use higher concentrations63
Intra-arterial can be used2
Intravesical no information found
Intraocular10,64,65 has been used; give 0.1 mL as intravitreal injection in the
affected eye
*High-dose methotrexate requires preservative-free methotrexate and leucovorin rescue.66
†Intrathecal methotrexate requires preservative-free methotrexate. See BC Cancer Policy III-50 Administration of High Alert
Medications by the Intrathecal Route via Lumbar Puncture or Ommaya Reservoir.

DOSAGE GUIDELINES:
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease,
response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count
(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to
cytotoxic/radiation therapy or with other toxicities.

Adults:
BC Cancer usual dose noted in bold, italics
Cycle Length:
Oral: 1 week67: 15-25 mg/m2 PO for one dose on day 1 and then day 3 or 4
(total dose per cycle 30-50 mg/m2 )

4 weeks68-71 2.5 mg PO once or twice a day for 2 consecutive days starting

on day 1 and 2 of each week*
(total dose per cycle 20-40 mg)

(*two non-consecutive days of the week have also been used for
metronomic or low-dose dosing)71,72

Intravenous: 1 week67: 40 mg/m2 IV for one dose on day 1

(total dose per cycle 40 mg/m2)

1-3 weeks73: 30-60 mg/m2 IV for one dose on day 1

(total dose per cycle 30-60 mg/m2)

1-4 weeks74,75: 1000-12000 mg/m2 IV over 4 hours for one dose on day 1
(total dose per cycle 1000-12000 mg/m2)
requires leucovorin rescue (see Special Precautions)

2 weeks59,60: 0.4 mg/kg/day IV for one dose on days 1 to 5

max 25 mg/day
(total dose per cycle 2 mg/kg; max 250 mg)

2 weeks76: 25 mg/m2 IV for one dose on day 1

(total dose per cycle 25 mg/m2)

BC Cancer Drug Manual© Page 12 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

BC Cancer usual dose noted in bold, italics

Cycle Length:
2 weeks12,77,78: 30 mg/m2 IV for one dose on day 1
(total dose per cycle 30 mg/m2)

2 weeks20: 100 mg/m2 IV for one dose and 300 mg/m2 IV over 4 hours for
one dose both on day 1
(total dose per cycle 400 mg/m2)
requires leucovorin rescue (see Special Precautions)

2 weeks19: 100 mg/m2 IV for one dose and 300 mg/m2 IV over 4 hours for
one dose both on day 8
(total dose per cycle 400 mg/m2)
requires leucovorin rescue (see Special Precautions)

2 weeks19: 1000 mg/m2 IV over 24 hours for one dose on day 8

(total dose per cycle 1000 mg/m2)
requires leucovorin rescue (see Special Precautions)

3 weeks18: 3000 mg/m2 IV over 4 hours for one dose on day 10

(total dose per cycle 3000 mg/m2)
requires leucovorin rescue (see Special Precautions)

4 weeks79,80: 40 mg/m2 IV for one dose on days 1 and 8

(total dose per cycle 80 mg/m2)

4 weeks81: 30 mg/m2 IV for one dose on days 1 and 15 and 22

(total dose per cycle 90 mg/m2)

Intramuscular: 2 weeks11,59,60: 50 mg IM for one dose on days 1, 3, 5, and 7 OR days 1, 3, 5,

and 8
(total dose per cycle 200 mg)

2 weeks60: 1 mg/kg IM for one dose on days 1, 3, 5, and 7 OR days 1, 3, 5,

and 8
(total dose per cycle 4 mg/kg)

weekly14: 15-30 mg IM for one dose on days 1-5

(total dose per cycle 75-150 mg)

weekly14: 50 mg IM for one dose on day 1 OR 25 mg IM for one dose twice

weekly
(total dose per cycle 50 mg)

Intrathecal: n/a 12 mg IT for one dose once or twice weekly82,83

(maximum two IT injections per week)

n/a 12-12.5 mg IT as part of combination therapy once weekly18,19

BC Cancer Drug Manual© Page 13 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

BC Cancer usual dose noted in bold, italics

Cycle Length:
Intraocular: 2-4 400 mcg/0.1 mL by intravitreal injection in the affected eye for one
weeks10,64,65: dose

Concurrent radiation: increased risk of soft tissue necrosis and osteonecrosis2

Dosage in myelosuppression: modify according to protocol by which patient is being treated; if no guidelines
available, refer to Appendix "Dosage Modification for Myelosuppression"

Dosage in renal failure: Suggested dose modifications84:

Creatinine clearance (mL/min) Methotrexate dose
61-80 75%
51-60 70%
10-50 30-50%
<10 avoid
Calculated creatinine clearance = N* x (140 - Age) x weight (kg)
serum creatinine in micromol/L
* For males N = 1.23; for females N=1.04

OR alternately, for creatinine clearance less than 100 mL/min, reduce methotrexate
dose proportionately to the reduction in creatinine clearance:16,17,85,86
e.g., CrCl ≥100 mL/min, give 100% of dose
CrCl = 85 mL/min, give 85% of dose
CrCl = 60 mL/min, give 60% of dose

Metronomic or low-dose dosing:

Suggested dose modifications:68,69,72
Creatinine clearance (mL/min) Methotrexate dose
>30 100%
15-30 50%
<15 avoid
Calculated creatinine clearance = N* x (140 - Age) x weight (kg)
serum creatinine in micromol/L
* For males N = 1.23; for females N=1.04

Dosage in hepatic failure: Suggested dose modifications84,87

Bilirubin or AST (units/L) Dose
(micromol/L)
50-85 3 x ULN 75 %
>85 - avoid

Dosage in dialysis88: hemodialysis: 50% dose

chronic ambulatory peritoneal dialysis (CAPD): no information found
continuous renal replacement therapy (CRRT): 30-50% dose

BC Cancer Drug Manual© Page 14 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

Children:
Cycle Length:
Oral, Intramuscular, 1-2 weeks: 7.5-30 mg/m2
Subcutaneous8:

Intravenous8: bolus or continuous n/a 10-33,000 mg/m2*

infusion (6-24 h)
*Doses above 100 to 300 mg/m2, which are usually administered by
continuous infusion, must be followed by leucovorin rescue.8

Intrathecal8: n/a 6 mg (age <1 yr)

8 mg (age 1 yr)
10 mg (age 2 yr)
12 mg (age ≥3 yr)

REFERENCES:

1. Mayne Pharma Canada Inc. LEUCOVORIN CALCIUM® Injection product monograph. Montreal, Quebec; 2003
2. Mayne Pharma (Canada) Inc. Methotrexate injection product monograph. Montreal, Quebec; 6 Dec 2003
3. Mayne Pharma. Apo-methotrexate tablet product monograph. Montreal, Quebec; 2003
4. Rose BD editor. Methotrexate. (accessed 5 April 2006). Waltham, Massachusetts: UpToDate®; 2006
5. McEvoy GK, editor. AHFS 2006 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; .
p. 1137-1145
6. Qin D, Ma J, Xiao J, et al. Effect of brain irradiation on blood-CSF barrier permeability of chemotherapeutic agents. Am J Clin
Oncol 1997;20(3):263-5
7. Joerger M, Huitema ADR, van den Bongard, H. J. G. D., et al. Determinants of the elimination of methotrexate and 7-hydroxy-
methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol 2005;62(1):71-80
8. Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, Pennsylvania: Lippincott Williams &
Wilkins; 2002
9. Lexi-Drugs® - Lexicomp Online (database on the Internet). Methotrexate. Wolters Kluwer Clinical Drug Information Inc.,
Available at: http://online.lexi.com. Accessed Aug 18, 2022
10. Benner JD, Dao D, Butler JW, et al. Intravitreal methotrexate for the treatment of proliferative vitreoretinopathy. BMJ Open
Ophthalmol 2019;4(1):1-5
11. Sita-Lumsden A, Short D, Lindsay I, et al. Treatment outcomes for 618 women with gestational trophoblastic tumours following
a molar pregnancy at the Charing Cross Hospital, 2000–2009. Br J Cancer 2012;107(11):1810-1814
12. Choueiri TK, Jacobus S, Bellmunt J, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin With
pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol
2014;32(18):1889-1894
13. Perry CP. Hepatotoxicity of chemotherapy. In UpToDate 14.3; Rose,Burton D. (Ed);, 2006. Available at: www.uptodate.com
14. Pfizer Canada-ULC. Methotrexate injection product monograph. Kirkland, Québec; July 8, 2019
15. Accord Healthcare Inc. Methotrexate injection product monograph. Kirkland, Québec; October 30, 2019
16. BC Cancer Agency Lymphoma Tumour Group. (LYHDMTXR) BCCA Protocol Summary for Treatment of Primary Intracerebral
Lymphoma with High Dose Methotrexate. Vancouver, British Columbia: BC Cancer Agency; 2004
17. BC Cancer Agency Lymphoma Tumour Group. (LYHDMTXP) BCCA Protocol Summary for Treatment of Leptomeningeal
Lymphoma with High Dose Methotrexate. Vancouver, British Columbia: BC Cancer Agency; 2004
18. BC Cancer Agency Lymphoma Tumour Group. (LYSNCC) BCCA Protocol Summary for Treatment of Burkitt Lymphoma with
Cyclophosphamide and Methotrexate. Vancouver, British Columbia: BC Cancer Agency; 2004
19. BC Cancer Agency Gynecologic Oncology Tumour Group. (GOTDHR) BCCA Protocol Summary for High Risk Gestational
Trophoblastic Cancer (GO9130) "MACE" using Cisplatin, Etoposide, Actinomycin D, Methotrexate, and Leucovorin. Vancouver,
British Columbia: BC Cancer Agency; 2005
20. BC Cancer Agency Gynecologic Oncology Tumour Group. (GOTDLR) BCCA Protocol Summary for Low Risk Gestational
Trophoblastic Cancer using Dactinomycin and Methotrexate. Vancouver, British Columbia: BC Cancer Agency; 2003
21. Wyeth Canada. Lederle LEUCOVORIN® calcium folinate tablets Product Monograph. Montreal, Quebec; 2004
22. LaCasce AS. Therapeutic use and toxicity of high-dose methotrexate. In: 2017 UpToDate®; Basow,Denise S. (Ed); updated
2Nov2016; accessed 3Apr2017. Waltham, Massachusetts: UpToDate®; Available at www.uptodate.com; 2016
23. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978;41(1):36-51

BC Cancer Drug Manual© Page 15 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

24. BC Cancer Agency Provincial Systemic Therapy Program. Systemic Therapy Update: Revised Methotrexate Levels for
Initiating Oral Leucovorin (LYCODOXMR, LYHDMRP, LYHDMTXP, LYHDMTXR, MOHDMTX). 16(1) ed. Vancouver, British
Columbia: BC Cancer Agency; January 2013
25. Tamara Shenkier MD. Medical Oncologist, BC Cancer Agency. Personal communication. June2006
26. Kremer JM. Major side effects of methotrexate. UpToDate, 2006. Available at: www.uptodate.com. Accessed 8 May, 2006
27. BC Cancer Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and
Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer; March 1 2021
28. BC Cancer. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults.
Vancouver, British Columbia: BC Cancer; 1 July 2020
29. Balk RA. Methotrexate-induced lung injury. UpToDate, 2006. Available at: www.uptodate.com. Accessed 8 May, 2006
30. Wen PY, Plotkin SR. Neurologic complications of cancer chemotherapy. UpToDate, 2006. Available at: www.uptodate.com.
Accessed 27 April, 2006
31. Protherics Inc. VORAXAZE® (glucarpidase; carboxypeptidase G2) product monograph. 2005
32. BTG International Inc. VORAXAZE® prescribing information. Brentwood, Tennessee USA; 03/ 2013
33. Widemann BC, Balis FM, Kempf-Bielack B, et al. High-dose methotrexate-induced nephrotoxicity in patients with
osteosarcoma. Cancer 2004;100(10):2222-32
34. National Institute for Occupational Safety and Health, (NIOSH). Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; September 2004. p. 31-40
35. National Institute for Occupational Safety and Health, (NIOSH). Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. Cincinnati, Ohio: NIOSH - Publications Dissemination; 25 March 2004. p. 71-83
36. Cancer Therapy Evaluation Program. Special Exception Protocol for the use of carboxypeptidase-G2 for MTX toxicity.
Rockville, MD: National Cancer Institute; 3 June 2004
37. Kremer JM. Methotrexate-induced hepatotoxicity. UpToDate, 2006. Available at: www.uptodate.com. Accessed 8 May, 2006
38. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott
Williams & Wilkins; 2001. p. 2640
39. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia:
Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27
40. Sanofi-Synthelabo. FASTURTEC® product information. Markham, Ontario; . 2004
41. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. E-Edition ed. Vancouver, British
Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2010. p. 93-94
42. Widemann BC, Hetherington ML, Murphy RF, et al. Carboxypeptidase-G2 rescue in a patient with high dose methotrexate-
induced nephrotoxicity. Cancer 1995;76(3):521-6
43. Wickersham R, Novak K, Schweain S editors. Drug Facts and Comparisons. St. Louis, Missouri: Wolters Kluwer Health, Inc;
2005
44. McEvoy GK. AHFS 2004 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2006.
p. 932-1168
45. Rose BD editor. Methotrexate/ Bile Acid Seqestrants. (accessed 26 April 2006). Waltham, Massachusetts: UpToDate®; 2006
46. Rose BD editor. Crystal-induced acute renal failure. UpToDate ed. Waltham, Massachusetts: UpToDate®; 2006
47. Rose BD editor. Cyclosporin/Methotrexate. UpToDate ed. Waltham, Massachusetts: UpToDate®; 2006
48. Hospira Healthcare Corporation. Methotrexate Injection USP® product monograph. Saint-Laurent, Quebec; 27 June . 2012
49. MICROMEDEX® 2.0 Drug Interactions (database on the Internet). Methotrexate. Thomson Reuters, updated periodically.
Available at: http://www.thomsonhc.com/micromedex2. Accessed 31July, 2013
50. Suzuki K, Doki K, Homma M, et al. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in
high-dose methotrexate therapy. Br J Clin Pharmacol 2008;67(1):44-49
51. Santucci R, Leveque D, Kemmel V, et al. Severe intoxication with methotrexate possibly associated with concomitant use of
proton pump inhibitors. Anticancer Res 2010;30:963-966
52. Drug Interaction Facts [database on the Internet]. Methotrexate. : Facts and Comparisons 4.0; 2006
53. eFacts. Methotrexate. : Facts and Comparisons; 2006
54. Accord Healthcare Inc. ACH-METHOTREXATE tablets product monograph. Kirkland, Québec; January 13, 2022
55. Apotex Inc. APO-METHOTREXATE tablets product monograph. Toronto, Ontario; June 30, 2021
56. Pharmascience Inc. pms-METHOTREXATE tablets product monograph. Montréal, Québec; May 16, 2019
57. Pfizer Canada-ULC. METHOTREXATE TABLETS product monograph. Kirkland, Québec; September 12, 2019
58. Maia M, Farah ME, Belfort RN, et al. Effects of intravitreal triamcinolone acetonide injection with and without preservative. Br J
Ophthalmol 2007;91(9):1122-1124
59. BC Cancer Gynecology Tumour Group. (GOTDLRM) BC Cancer Protocol Summary for Therapy for Low Risk Gestational
Trophoblastic Cancer using Methotrexate. Vancouver, British Columbia: BC Cancer; September 1 2022
60. Braga A, de Souza Hartung Araújo, C., Ribeiro Mora PA, et al. Comparison of treatment for low-risk GTN with standard 8-day
MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend. Gynecol Oncol 2020;156(3):598-605
61. Brigitte Vachon. Clinical Specialist, Pfizer/Hospira Healthcare Corporation. Personal communication. 15 December2015
62. Dorr RT, Von-Hoff DD. Cancer chemotherapy handbook. 2nd ed. Norwalk, Connecticut: Appleton & Lange; 1994. p. 27-28,123
63. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical Practice Guidelines for the Prevention and Treatment of Cancer
Therapy-Induced Oral and Gastrointestinal Mucositis. Supplement to Cancer 2004;100(9):2026-2046
64. Bae JH, Lee SC. Effect of intravitreal methotrexate and aqueous humor cytokine levels in refractory retinal vasculitis in Behcet
disease. Retina 2012;32(7):1395-1402

BC Cancer Drug Manual© Page 16 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023
 Methotrexate

65. Yeh S, Wilson DJ, Casey Eye Institute Portland Oregon. Correspondence: Combination intravitreal rituximab and methotrexate
for massive subretinal lymphoma. Eye 2010;24(10):1625-1626
66. Trissel L. Handbook on injectable drugs. 13th ed. Bethesda, Maryland: American Society of Health-System Pharmacists; 2005.
p. 990
67. BC Cancer Agency Head and Neck Tumour Group. (HNM) BCCA Protocol Summary for Head and Neck Cancer Using
Methotrexate as Standard Therapy. Vancouver, British Columbia: BC Cancer Agency; 2005
68. Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer:
antitumor activity and correlation with vascular endothelial growth factor levels. Ann.Oncol. 2002;13(1):73-80
69. Gebbia V, Boussen H, Valerio MR. Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment
for patients with metastatic breast carcinoma. Anticancer Res. 2012;32(2):529-536
70. BC Cancer Agency Breast Tumour Group. (BRAVCMPO) BCCA Protocol Summary for Palliative Therapy for Metastatic Breast
Cancer Using Metronomic Low-Dose Oral Cyclophosphamide. Vancouver, British Columbia: BC Cancer Agency; 1 July 2012
71. Orlando L, Cardillo A, Rocca A, et al. Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic
breast cancer. Anticancer Drugs 2006;17(8):961-967
72. Colleoni M, Orlando L, Sanna G, et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus
thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann.Oncol. 2006;17(2):232-238
73. BC Cancer Agency Lymphoma Tumour Group. (LYPALL) BCCA Protocol Summary for Lymphoma Palliative Chemotherapy.
Vancouver, British Columbia: BC Cancer Agency; 2005
74. BC Cancer Agency Miscellaneous Origin Tumour Group. (UMOHDMTX) BCCA Protocol Summary for Treatment of Meningeal
Disease (Miscellaneous Tumour Origins) using High Dose Methotrexate with Leucovorin Rescue. Vancouver, British Columbia: BC
Cancer Agency; 1999
75. BC Cancer Agency Sarcoma Tumour Group. (OSHDMTX) BCCA Protocol Summary for Treatment of Osteosarcoma Using
High Dose Methotrexate with Leucovorin Rescue. Vancouver, British Columbia: BC Cancer Agency; 2000
76. BC Cancer Agency Kaposi's Sarcoma Tumour Group. (KSVB) BCCA Protocol Summary for Palliative Treatment for Kaposi's
Sarcoma using Vinblastine Alternating with Vincristine. Vancouver, British Columbia: BC Cancer Agency; 2002
77. Plimack ER, Hoffman-Censits J, Viterbo R, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe,
effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with
molecular correlates of response and toxicity. J Clin Oncol 2014;32(18):1895-1901
78. BC Cancer Genitourinary Tumour Group. (GUBDDMVAC) BC Cancer Protocol Summary for Neoadjuvant Treatment of
Urothelial Cancer Using Dose-dense Methotrexate, vinBLAStine, DOXOrubicin and CISplatin. Vancouver, BC: BC Cancer; August
1 2022
79. BC Cancer Agency Breast Tumour Group. (BRAJCMFPO) BCCA Protocol Summary for Adjuvant Therapy of Premenopausal
High Risk Breast Cancer using Cyclophosphamide (oral), Methotrexate, and Fluorouracil. Vancouver, British Columbia: BC Cancer
Agency; 1999
80. BC Cancer Agency Breast Tumour Group. (BRAVCMFPO) BCCA Protocol Summary for Palliative Therapy for Advanced
Breast Cancer using Cyclophosphamide (oral), Methotrexate, and Fluorouracil. Vancouver, British Columbia: BC Cancer Agency;
2004
81. BC Cancer Agency Genitourinary Tumour Group. (GUMVAC) BCCA Protocol Summary for Transitional Cell Cancer of the
Urothelium using Methotrexate, Vinblastine, Doxorubicin, and Cisplatin. Vancouver, British Columbia: BC Cancer Agency; 2003
82. BC Cancer Agency Miscellaneous Origin Tumour Group. (MOIT) BCCA Protocol Summary for Solid Tumours Using Intrathecal
Methotrexate and/or Thiotepa and/or Cytarabine. Vancouver, British Columbia: BC Cancer Agency; 2005
83. BC Cancer Agency Lymphoma Tumour Group. (LYIT) BCCA Protocol Summary for Treatment of Lymphoma using Intrathecal
Methotrexate and Cytarabine. Vancouver, British Columbia: BC Cancer Agency; 2004
84. Rose BD editor. Methotrexate. UpToDate 17.3 ed. Waltham, Massachusetts: UpToDate®; 2010
85. Batchelor T, Carson K, O'Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a
report of NABTT 96-07. J Clin Oncol 2003;21(6):1044-9
86. BC Cancer Agency Lymphoma Tumour Group. (LYHDMRP) BCCA Protocol Summary for Treatment of Primary Intracerebral
Lymphoma with High Dose Methotrexate and Rituximab. Vancouver, British Columbia: BC Cancer Agency; 1 May 2009
87. Floyd J, Mirza I, Sachs B, et al. Hepatoxicity of Chemotherapy. Sem Onc 2006;33(1):50-67
88. Aronoff GR, Brier ME, Berns JS, Bennett W. The Renal Drug Book 2006. Available at: http://www.kdp-
baptist.louisville.edu/renalbook/expand.asp?ID=1436; Accessed 4 May 2006

BC Cancer Drug Manual© Page 17 of 17 Methotrexate

This document may not be reproduced in any form without the express written permission of BC Cancer Provincial
Pharmacy.
Developed: September 1994; Revised: August 2006
Limited Revision: 1 July 2023