methotrexate

Appearance:

Yellow tablets or clear, yellow liquid for injection

Monograph Name:

methotrexate

Monograph Body:

Drug Monograph

A - Drug Name

methotrexate

B - Mechanism of Action and Pharmacokinetics

Methotrexate and its active metabolites compete for the folate binding site of the enzyme dihydrofolate reductase. Folic acid must be reduced to tetrahydrofolic acid by this enzyme for DNA synthesis and cellular replication to occur. Competitive inhibition of the enzyme leads to blockage of tetrahydrofolate synthesis, depletion of nucleotide precursors, and inhibition of DNA, RNA and protein synthesis. Methotrexate also inhibits thymidylate synthase and the transport of reduced folates into the cell. Methotrexate is cell cycle phase-specific (S phase).

Absorption

Peak serum levels are achieved in 1-2 h (PO) and 30-60 min (IM).

Bioavailability

oral: 60% bioavailability at doses <30 mg/m² in most patients. Significantly less bioavailability at > 80 mg/m². Bioavailability decreased by food and milk.

Distribution

Highest levels in kidney, gallbladder, spleen, liver and skin, retained in kidney and liver for prolonged periods. Methotrexate crosses the placenta, is found in breast milk and malignant effusions. Some accumulation may occur with repeated daily dosing, especially in liver.

Cross blood brain barrier?

poorly

PPB

50 %

Metabolism

Methotrexate is partially metabolized by intestinal flora after oral administration.

Low dose methotrexate does not appear to undergo significant metabolism. Following high dose treatment, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolases. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of polyglutamates may remain in tissues for extended periods. Methotrexate also undergoes minor metabolism into 7-hydroxymethotrexate (with lower solubility); accumulation may become significant after high dose methotrexate.

Active metabolites

Polyglutamates

Inactive metabolites

Yes, including 7-hydroxy-methotrexate

Elimination

Excreted principally by the kidney (80-90%) by glomerular filtration and active tubular secretion; biliary excretion is < 10%, significant inter- and intrapatient variability. Clearance is delayed in the presence of a third compartment fluid collection (i.e. pleural effusion, ascites). Enterohepatic recirculation of methotrexate may occur. Clearance relates inversely with dose.

Urine

80-90% excreted unchanged

Half-life

3-10 hours (low dose, < 30mg/m²)

8-15 hours (high dose)

C - Indications and Status

Health Canada Approvals:

Breast cancer
Bladder cancer
Choriocarcinoma
Gastric cancer
Head and neck cancer
Osteogenic sarcoma
Non-Hodgkin lymphoma (intermediate and high grade, Burkitt)
Advanced stages of childhood lymphoma (III and IV, St. Jude's Childrens' Research Hospital Staging System)
Acute lymphoblastic leukemia
Advanced stages of mycosis fungoides (cutaneous T-cell lymphoma)
Metastasis of unknown primary
Leptomeningeal spread of malignancies (carcinomatosis/leukemia/lymphoma)

Refer to the product monograph for a full list and details of approved indications.

Other Uses:

Gestational Trophoblastic Disease
Desmoid and Giant Cell tumour sarcoma
Hematological malignancies (acute myeloid leukemia, acute promyelocytic leukemia, myeloma, T-cell lymphoma, low grade Non-Hodgkin lymphoma)

D - Adverse Effects

Emetogenic Potential:

Moderate (IV doses ≥ 250 mg/m2)
Low (IV doses > 30 and < 250 mg/m2)
Minimal (IV doses ≤ 30mg/m2 or PO doses)

Extravasation Potential: Minimal

The incidence and severity of side effects vary depending on the dose, frequency of administration and the duration of exposure to significant blood methotrexate levels to the target organs. Side effects, including severe or life-threatening adverse effects and post-marketing, are listed in the table below.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arterial thromboembolism (rare)	E
	Hypotension (rare)	E
	Pericarditis , pericardial effusion (rare)	E
	Venous thromboembolism (rare)	E
Dermatological	Alopecia (occasional)	E
	Erythema multiforme (rare)	E
	Photosensitivity (rare)	E
	Radiation recall reaction	I E
	Rash (1 to <10%; may rarely be severe)	I E
	Skin hyperpigmentation (rare)	E
	Skin hypopigmentation	E
	Stevens-Johnson syndrome (rare)	E
	Toxic epidermal necrolysis (rare)	E
Gastrointestinal	Anorexia (≥10%)	E
	Diarrhea (1 to <10%; especially 24-48h after administration)	E
	Dyspepsia (≥10%)	E
	GI perforation (rare)	E
	Mucositis (≥10%) (may be severe)	E
	Nausea, vomiting (10%) (dose-dependent)	I
General	Fatigue (1 to <10%)	E
Hematological	↓ Immunoglobulins (rare)	E
	Myelosuppression ± infection, bleeding (1 to <10%)	E
	Other - Aplastic anemia (rare)	E
Hepatobiliary	↓ albumin (rare)	E
	Cirrhosis (or hepatic fibrosis; with long-term, low-dose use) (<1%)	L
	↑ LFTs (15%) (transient)	E
	Pancreatitis (rare)	E
Hypersensitivity	DRESS syndrome (rare)	E
	Hypersensitivity (rare)	I
Infection	Opportunistic infection or viral reactivation (rare)	E
Metabolic / Endocrine	Diabetes mellitus (rare)	E
	Tumor lysis syndrome (rare)	I
Musculoskeletal	Fracture (rare)	D
	Musculoskeletal pain (rare)	E
	Osteoporosis (rare)	D
	Other - osteonecrosis (rare, secondary to lymphoproliferative disorders)	E D
Neoplastic	Lymphoma (secondary) (low-grade; rare)	L
Nervous System	Cognitive disturbance (rare)	E
	Dizziness (rare)	E
	Headache (1 to <10%)	E
	Leukoencephalopathy (rare; acute or chronic)	L
	Seizure (rare)	E
Ophthalmic	Blurred vision (rare; transient visual changes)	E
	Conjunctivitis (rare)	E
Renal	Nephrotoxicity (especially with high doses; rare)	E
	Proteinuria (rare)	E
Reproductive and breast disorders	Infertility (rare)	E D
	Irregular menstruation (rare)	E D
	Oligospermia (rare)	E D
Respiratory	Other - Alveolar hemorrhage (rare)	E
	Pneumonitis (1%)	E
Vascular	Vasculitis (rare; including allergic)	I E

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The most common adverse effects are stomatitis, myelosuppression and gastrointestinal effects such as nausea. Toxicity is increased with prolonged duration of exposure as well as increased dose, and exacerbated by renal failure, NSAID usage, 3rd space collections and dehydration. Consider monitoring serum levels with any dose in such circumstances.

Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g., some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.

Risk factors for stomatitis include renal impairment, irradiation to the head and neck area and prolonged infusion. Administration of leucovorin decreases the risk of toxicity to the gastrointestinal tract.

Severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis have been reported and may be fatal. These reactions are not dose-dependent and may occur within days of administration of oral, IM or IV methotrexate. Recovery has been reported with treatment discontinuation.

Skin cancer has been reported in psoriasis or mycosis fungoides patients, who received concomitant methotrexate and psoralen plus ultraviolet light therapy (PUVA).

Renal toxicity may be related to precipitation of methotrexate and 7-OH methotrexate (less soluble than methotrexate) in the renal tubules and collecting ducts. Methotrexate was found to be 10 times less soluble in acidic urine than urine at pH 7. The risk of renal failure due to high-dose methotrexate (>1 g/m²) can be minimized by brisk diuresis, alkalinization of the urine (adjust urinary pH with IV sodium bicarbonate to maintain pH > 7), and monitoring of creatinine and serum methotrexate levels.

Acute elevation of hepatic enzymes is usually transient and asymptomatic. Decrease in serum albumin or persistent liver abnormalities may indicate serious liver toxicity. This occurs more frequently in patients receiving moderate to high methotrexate doses. Chronic hepatotoxicity (fibrosis or cirrhosis) is more common in patients receiving long term (usually more than 2 years) and after a cumulative dose of at least 1.5g, and may be fatal. Reactivation or worsening of hepatitis B and C infections, including fatal cases, have been observed with methotrexate. Some cases occurred after treatment discontinuation.

Clearance of methotrexate is delayed in the presence of fluid in the third space (e.g., pleural effusions, ascites), and toxicity may be enhanced. It is recommended that such effusions be evacuated before treatment with methotrexate.

Myelosuppression may develop with any dosage schedule, but is more severe with high doses, daily administration of lower doses, in malnourished patients, in patients with decreased renal function and in patients with effusions, ascites or significant edema. Administration of leucovorin decreases the risk of myelosuppression when given with high-dose methotrexate. The nadir of leukocytes, neutrophils and platelets usually occurs between 4 to 13 days after an IV bolus, followed by recovery 2-4 weeks after the dose. Occasionally, the decrease in leukocytes and neutrophils may present as 2 nadirs; the first after 4-7 days and the second after 12-21 days, followed by recovery.

Methotrexate has the ability to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the methotrexate. Recurrent injury to a previously radiated site may occur weeks to months following radiation.

Chemical meningitis may occur with intrathecal methotrexate, beginning within 12 hours after injection, and may persist for ≥ 1 week. This is characterized by stiff neck, headache, back pain, nausea and vomiting, fever and lethargy. Administration at intervals of less than 1 week may result in increased subacute toxicity. The syndrome may be subacute (paraplegias/paresthesia) or chronic (leukoencephalopathy), and transient or permanent. Risk factors include advanced age, methotrexate dose used, presence of overt meningeal leukemia, or concurrent cranial radiation.

Other CNS toxicities include an acute or subacute encephalopathy consisting of behavioural abnormalities, focal sensorimotor signs, abnormal reflexes or hemiparesis, occasionally with seizures, in patients receiving high-dose methotrexate. The exact cause is unknown. It has occurred within 2-4 weeks of high-dose methotrexate treatment, and is usually transient.

Delayed neurotoxicity, occurring months to years after methotrexate, can be severe and even fatal. This syndrome, a progressive leukoencephalopathy, is rare and usually associated with some combination of cranial irradiation, systemic methotrexate and intrathecal methotrexate. Clinical signs are those of progressive neurologic deterioration and include confusion, ataxia, dementia, limb spasticity, coma, seizures and death. Prognosis with leukoencephalopathy is variable; most patients have continued neurological deficits. The syndrome may be partially reversible if methotrexate is discontinued. The risk of leukoencephalopathy is increased with increasing cumulative doses of methotrexate (may also occur with low oral doses), by concurrent cranial radiation and when methotrexate IT is used to treat meningeal tumour rather than for prophylaxis.

Pulmonary toxicity can be immediate or delayed. It is not always fully reversible and may be fatal. The immediate toxicity is associated with pneumonitis, acute pleuritic chest pain and chronic non-productive cough. Pulmonary toxicity does not appear to be dose-related. It appears to be schedule-dependent, since daily or weekly administration schedules are more toxic than every 2-4 week administration schedules, but there does not appear to be a threshold. Corticosteroids may hasten recovery.

E - Dosing

Evaluate any pre-existing hepatitis B and C before starting treatment.

Methotrexate is frequently administered in combination with other drugs. Hydration, urine alkalinization, leucovorin rescue and monitoring of levels may be required depending on the dose used.

Risk factors for elevated or prolonged methotrexate levels include third space fluid accumulation, GI obstruction, previous cisplatin therapy, dehydration, aciduria and impaired renal function.

Table 1:

100-500 mg/m²

500-1000 mg/m²

≥ 1000mg/m²

Hydration and alkalinization of urine	Consider*	Yes	Yes
Leucovorin rescue	Consider*	Yes	Yes
Methotrexate levels		Consider*	Yes

* especially if risk factors

Adults:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.

Some examples include:

Oral (for administration of low doses):

Q 2-3 w: 10-30 mg/day for 5 days
Q4w: 40 mg/m² days 1 and 8

Intravenous (low doses may be given as IM depending on the protocol):

Q4w: 40 mg/m² day 1 and 8;
Q4w: 30 mg/m² days, 1, 15, 22
Q3w: 30 mg/m² days 1 and 8
Weekly: 30 – 60 mg/m²
Q3-4w: 120 mg/m² - 1.5 g/m² (also refer to table 1)
Depend on protocol: 3.5 g/m² – 12 g/m² (also refer to table 1)

Intrathecal:

Q2-7d: 12 mg in preservative-free NS
Dose is the same whether given intrathecally or into an Ommaya (intraventricular) reservoir. Elderly patients may require a reduced dose.

Dosage with Toxicity:

Toxicity	Action
Grade 4 neutropenia or thrombocytopenia, febrile neutropenia or thrombocytopenic bleeding	Hold until recovery * and then reduce by 25%
Grade 3 non-hematologic/organ	Hold until recovery * and then reduce by 25%
Grade 4 non-hematologic/organ	Discontinue
Suspected pneumonitis	Hold, investigate appropriately and discontinue if confirmed
Leukoencephalopathy, hepatic fibrosis, viral reactivation	Discontinue
* until ANC ≥ 1.5 x 10⁹/L, platelets ≥ 100 x 10⁹/L and other toxicity ≤ grade 2

Overdose or Severe Toxicity: Can be treated with prompt leucovorin rescue. Acute, intermittent dialysis with a high-flux dialyzer has also been used. Hydration and urinary alkalinization may prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. There have been case reports of intravenous carboxypeptidase G2 use in cases of overdose to hydrolyze methotrexate to inactive metabolites and hasten clearance.

Dosage with Hepatic Impairment:

Bilirubin (µmol/L)		Transaminases	% usual dose
2.5 - 4 x ULN	or	> 3 x ULN	75%
> 4 x ULN			DISCONTINUE

Dosage with Renal Impairment:

Methotrexate is contraindicated in patients with severe renal impairment. The following are recommended starting doses in patients with renal impairment. May require further dose adjustment due to wide inter-subject variability in pharmacokinetics.

Creatinine clearance (mL/min)	Starting dose (% usual dose)
>80	100%
80	75%
60*	60%
50*	55%
<50	Use alternative therapy
*High-dose methotrexate treatment should be given only if Clcr > 60 mL/min.

Dosage in the elderly:

Methotrexate has not been well studied in the elderly. It should be used with extreme caution because of likely renal and hepatic impairment and reduced folate stores in the elderly. Monitor closely. Consider lower doses with intrathecal usage.

Children:

Refer to protocols being used. Methotrexate solutions containing benzyl alcohol should not be used in neonates (less than 1 month of age).

F - Administration Guidelines

Preservative-free methotrexate must be used for intrathecal, intracerebroventricular, high dose administration, or in neonates (less than one month of age).
Do not admix with 5FU, prednisolone, KCl or other drugs unless compatibility data are available.
Avoid contact with acidic solutions since methotrexate precipitation may occur.
May be given IM or by IV push, depending on the dose and regimen.
May also be admixed in Normal Saline or 5% dextrose; the manufacturer recommends dilution to a concentration of 0.4 to 2 mg/mL. Infuse IV over 30 minutes to 24 hours, depending on the regimen.
Store unopened vials between 15 to 25⁰C. Protect from light.

Methotrexate (High dose >1g/m²) - The following steps are MANDATORY:

Preservative-free methotrexate formulation must be used
Alkalinization and hydration (example):
- Hydrate with 1000 mL/m² of IV fluid over 6 hours before starting methotrexate infusion. Continue hydration at 125mL/m²/h (3L/m²/day) during the methotrexate infusion, and for 2 days after the infusion is completed.
- Alkalinize urine, starting 6-12 hours before Methotrexate, with IV or PO Sodium Bicarbonate; ensure urine pH > 7 before starting methotrexate. Maintain urine pH > 7.
Continue hydration and alkalinization during methotrexate infusion and for 48h after completion of Methotrexate infusion
Leucovorin rescue to start 24-36 hours after start of Methotrexate; continue until serum levels drop below 0.1 micromolar (toxic range depends on local policy and methotrexate assays used). Refer to Leucovorin monograph).

Intrathecal Methotrexate:

Preservative-free formulation must be used
Mix with preservative-free diluent using strict aseptic technique.

Oral Methotrexate:

Avoid taking methotrexate tablets with food or milk, as absorption may be reduced.

G - Special Precautions

Contraindications:

Patients who are hypersensitive to methotrexate or any components of the formulation or container
Patients with severe renal impairment including end stage renal disease with and without dialysis
Women of childbearing potential until pregnancy is excluded
Breastfeeding women
Concomitant use with nitrous oxide anesthesia
Formulations containing benzyl alcohol are contraindicated for use in intrathecal, intracerebroventricular, high-dose therapy, or neonates (less than one month of age)

Refer to the product monograph for contraindications related to the treatment of psoriasis or rheumatoid arthritis.

Other Warnings/Precautions:

Use with extreme caution in patients with a history of peptic ulceration or ulcerative colitis and in patients with poor performance status, with active infection, impaired bone marrow function, prior or current wide field radiation, chronic liver disease, cirrhosis or with mild or moderate renal impairment.
Avoid the use of live vaccines.
Immunization may be ineffective when given during methotrexate treatment.
Rare hypogammaglobulinemia has been reported.
Not recommended in patients with active or chronic hepatitis B or C infection.
Use caution with administration of packed red blood cells and methotrexate. Increased toxicity, probably due to prolonged high methotrexate concentrations, have been observed in patients receiving 24-hour methotrexate infusion and subsequent transfusion.
Folate deficiency states may increase methotrexate toxicity.
Methotrexate tablets containing lactose should not be used in patients with hereditary lactose/galactose/lactase disorders.
Patients with relevant third space fluid collections have prolonged excretion of methotrexate levels and a resulting increase in toxicity. Evacuation of fluid collections and close monitoring of serum levels are recommended in such patients.
There may be an increased risk of tissue necrosis or osteonecrosis when methotrexate is given concurrently with radiotherapy.

Other Drug Properties:

Carcinogenicity: Possible

Lymphoma may occur in patients receiving low-dose methotrexate. This may regress after stopping methotrexate.

Pregnancy and Lactation:

Embryotoxicity: Yes
Teratogenicity: Yes

Methotrexate is contraindicated in pregnancy and breastfeeding. It has been reported to cause fetal death and/or congenital anomalies. Abortion is likely when administered to a pregnant woman. Adequate contraception should be used in both sexes, during treatment and for at least 6 months after the last dose.
Breastfeeding: Contraindicated

Methotrexate is secreted in human breast milk in small concentrations and may accumulate in neonatal tissues.
Fertility effects: Yes

H - Interactions

Methotrexate given concurrently with radiotherapy may increase the risk of soft tissue necrosis or osteonecrosis.

AGENT	EFFECT	MECHANISM	MANAGEMENT
Acitretin/etretinate	Risk of hepatotoxicity observed in patients on etretinate and methotrexate	Unknown	Contraindicated.
Alcohol	↑ hepatotoxicity	Additive	Avoid alcohol intake.
Asparaginase	↑ hepatotoxicity	Additive effect on liver	Monitor liver function.
Asparaginase	↓ effect of methotrexate if asparaginase is given immediately prior to or with methotrexate; ↑ effect of methotrexate when asparaginase is given after methotrexate	Suppression of asparagine concentrations; asparaginase decreases methotrexate cellular uptake or inhibits the cell replication necessary for methotrexate action	Give asparaginase 9-10 days before or 24 hours after methotrexate, or refer to specific protocol.
Carboxypeptidase-G	↓ toxicity of methotrexate	Cleaves the methotrexate molecule to inactive fragments	May be useful to treat IT methotrexate overdose or delayed methotrexate toxicity.
Certain oral antibiotics (tetracycline, chloramphenicol, or non-absorbable: neomycin, polymyxin B, nystatin, vancomycin)	May ↓ methotrexate serum concentration	↓ intestinal absorption of methotrexate, interferes with enterohepatic circulation	Observe for ↓ therapeutic response of methotrexate.
Cyclosporine	↑ methotrexate and cyclosporine toxicity	Blocks methotrexate oxidation to inactive metabolite; affects elimination of both drugs	If must use together, monitor patient closely for cyclosporine and methotrexate toxicity.
Cytarabine IV	Severe neurological reactions in children and adolescents	Unknown	Caution.
Digoxin	↓ digoxin effect	↓ absorption	Monitor digoxin therapeutic effects.
Hepatotoxins (e.g. leflunomide, retinoids, azathioprine, sulfasalazine)	↑ risk of hepatic toxicity (and myelosuppression – leflunomide)	Additive	Avoid concomitant use.
Highly protein bound drugs (i.e., tetracyclines, sulfonylureas, phenytoin, warfarin, etc)	↑ methotrexate toxicity	Displacement and ↑ methotrexate bioavailability	Use with caution and monitor methotrexate levels (if applicable) or avoid concomitant use.
Leucovorin and high doses of folic acid	↓ toxicity of methotrexate	"Rescues" cells from toxic effects of methotrexate	Administer leucovorin within 24-36 hours after start of methotrexate; refer to local protocols.
Nephrotoxic drugs (e.g. cisplatin, aminoglycosides, amphotericin B)	↑ methotrexate toxicity	↓ clearance of methotrexate	Caution; monitor for toxicity if co-administration cannot be avoided.
Nitrous oxide anesthesia	Severe myelosuppression, stomatitis, nephrotoxicity; Neurotoxicity (with IT methotrexate)	↑ methotrexate effect on folate metabolism	Contraindicated.
NSAIDs	↑ methotrexate toxicity due to prolonged serum levels, possibly fatal hematologic and GI toxicity	↓ renal excretion and/or tubular secretion of methotrexate	Avoid use prior to or in combination with high dose methotrexate. Caution when low doses of methotrexate are used (e.g. in rheumatoid arthritis).
Penicillins, ciprofloxacin	↑ methotrexate effect and toxicity	↓ renal excretion and/or tubular secretion of methotrexate	Caution; monitor carefully for toxicity if coadministration cannot be avoided.
PPIs (e.g. omeprazole, pantoprazole, etc)	↑ methotrexate toxicity, since may elevate and prolong serum levels of methotrexate and/or its metabolite	Inhibits renal elimination of methotrexate or its metabolite	Avoid concomitant use with high-dose methotrexate, especially in renal impairment. Caution with concurrent low-dose methotrexate. Consider use of ranitidine.
Procarbazine	↑ nephrotoxicity	Unknown	Allow at least 72 hours between the last dose of procarbazine and the start of high dose methotrexate.
Salicylates	↑ methotrexate toxicity	↓ renal excretion and/or tubular secretion of methotrexate, displace methotrexate from protein binding	Avoid concomitant use with high-dose methotrexate. Monitor for toxicity if coadministration cannot be avoided. Doses used for cardiovascular events prophylaxis are unlikely to be of concern.
Sulfonamides (e.g. sulfamethoxazole, cotrimoxazole)	↑ methotrexate toxicity	↓ renal excretion and/or tubular secretion of methotrexate, additive anti-folate effect, displace methotrexate from protein binding	Consider avoiding concurrent use of therapeutic doses of sulfonamide antibiotics. Monitor for toxicity if coadministration cannot be avoided.
Theophylline	↑ theophylline effect	↓ clearance	Monitor theophylline levels.
Thiazide diuretics, triameterene	↑ myelosuppression (also ↓ folate levels with triameterene)	Unknown	Consider alternative antihypertensive therapy.
Trimethoprim	↑ methotrexate toxicity	Additive antifolate effect and/or ↓ tubular secretion	Consider avoiding concurrent use of therapeutic doses of trimethoprim. Monitor for toxicity if co-administration cannot be avoided.
Thiopurines (azathioprine, mercaptopurine)	↑ thiopurines effect	↓ metabolism of thiopurines	May require thiopurine dose adjustment with high-dose methotrexate.

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
Methotrexate levels when dose > 1 g/m², or in patients with third space fluid accumulation, GI obstruction, previous cisplatin therapy, dehydration or renal impairment. Draw creatinine and methotrexate levels starting 24 hours after methotrexate initiation and at least once daily until methotrexate level is < 0.1 µM (toxic range depends on local policy and methotrexate assays used).	As per local protocols
CBC	Baseline and before each cycle
Liver function tests	Baseline and before each cycle
Renal function tests	Baseline and before each cycle
Chest x-ray	Baseline and as clinically indicated
Clinical assessment of infection, bleeding, GI, skin, pulmonary, or CNS toxicity	At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Monitor Type	Monitor Frequency
Lung function tests if pulmonary toxicity suspected	As clinically indicated

J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

methotrexate - oral tablets

K - References

Antiemesis guidelines. National Comprehensive Cancer Network. Version 1.2012.

Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).

Capizzi RL. Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells. Cancer Treat Rep 1981;65 Suppl 4:115-21.

Korstanje MJ, van Breda Vriesman CJP, van de Staak WJ. Cyclosporin and methotrexate: a dangerous combination. J Am Acad Dermatol 1990; 23: 320-321

McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 928, 1154-9.

Methotrexate: e-Drugdex®. Micromedex Healthcare Series.

Methotrexate: Lexi-comp® Drug Interactions.

Methotrexate Safety information. U.S. Food and Drug Administration, December 21, 2011.

Orr LE. Potentiation of myelosuppression from cancer chemotherapy and thiazide diuretics. Drug Intell Clin Pharm 1981; 15: 967-70.

Pizzo PA, Poplack DG, Bleyer WA. Neurotoxicities of current leukemia therapy. Am J Pediatr Hematol Oncol 1979;1(2):127-40.

Prescribing information: Soriatane® (acitretin). Stiefel (US), March 2011.

Price P, Thompson H, Bessell EM, et al. Renal impairment following the combined use of high-dose methotrexate and procarbazine. Cancer Chemother Pharmacol 1988;21(3):265-7.

Product Monograph: Methotrexate Injection. Pfizer Canada, July 2011.

Product Monograph: Methotrexate Tablets. Apotex Inc., August 2011.

Product Monograph: Methotrexate Injection. Accord Healthcare (UK). June 2019.

Product Monograph: Methotrexate Injection. Hospira (US). April 2018 and March 2021.

Product Monograph: Cipro® (ciprofloxacin). Bayer Corp, 2009.

Rubnitz JE, Relling MV, Harrison PL, et al. Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia. Leukemia. 1998;12(8):1176.

Schornagel JH, McVie JG. The clinical pharmacology of methotrexate. Cancer Treatment Reviews 1983;10(1):53-75.

Schwartz S, Borner K, Müller K, et al. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007 Nov;12(11):1299-308.

Walker RW, Allen JC, Rosen G, et al. Transient cerebral dysfunction secondary to high-dose methotrexate. J Clin Oncol. 1986;4(12):1845.

Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Natl Cancer Inst. 2004;96(20):1557-9.

November 2022 Modified Pharmacokinetics, Indications, Adverse Effects, Dosage in renal impairment, Contraindications, Precautions, Pregnancy/lactation, Interactions and Monitoring sections

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.

References:

Antiemesis guidelines. National Comprehensive Cancer Network. Version 1.2012.

Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).

Capizzi RL. Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells. Cancer Treat Rep 1981;65 Suppl 4:115-21.

Korstanje MJ, van Breda Vriesman CJP, van de Staak WJ. Cyclosporin and methotrexate: a dangerous combination. J Am Acad Dermatol 1990; 23: 320-321

McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 928, 1154-9.

Methotrexate: e-Drugdex®. Micromedex Healthcare Series.

Methotrexate: Lexi-comp® Drug Interactions.

Methotrexate Safety information. U.S. Food and Drug Administration, December 21, 2011.

Orr LE. Potentiation of myelosuppression from cancer chemotherapy and thiazide diuretics. Drug Intell Clin Pharm 1981; 15: 967-70.

Pizzo PA, Poplack DG, Bleyer WA. Neurotoxicities of current leukemia therapy. Am J Pediatr Hematol Oncol 1979;1(2):127-40.

Prescribing information: Soriatane® (acitretin). Stiefel (US), March 2011.

Price P, Thompson H, Bessell EM, et al. Renal impairment following the combined use of high-dose methotrexate and procarbazine. Cancer Chemother Pharmacol 1988;21(3):265-7.

Product Monograph: Methotrexate Injection. Pfizer Canada, July 2011.

Product Monograph: Methotrexate Tablets. Apotex Inc., August 2011.

Product Monograph: Methotrexate Injection. Accord Healthcare (UK). June 2019.

Product Monograph: Methotrexate Injection. Hospira (US). April 2018 and March 2021.

Product Monograph: Cipro® (ciprofloxacin). Bayer Corp, 2009.

Rubnitz JE, Relling MV, Harrison PL, et al. Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia. Leukemia. 1998;12(8):1176.

Schornagel JH, McVie JG. The clinical pharmacology of methotrexate. Cancer Treatment Reviews 1983;10(1):53-75.

Walker RW, Allen JC, Rosen G, et al. Transient cerebral dysfunction secondary to high-dose methotrexate. J Clin Oncol. 1986;4(12):1845.

Widemann BC, Balis FM, Shalabi A, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Natl Cancer Inst. 2004;96(20):1557-9.

Info Sheet Name:

methotrexate (patient)

Info Sheet Introduction:

For treating many types of cancer, including some breast or bladder cancers, lymphomas, leukemias or sarcomas

Info Sheet Date: Lundi, juin 20, 2022 Info Sheet body:

Medication Information Sheet

methotrexate (meth-oh-TREX-ate)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Appearance:

Yellow tablets or clear, yellow liquid for injection

What is this medication for?

For treating many types of cancer, including some breast or bladder cancers, lymphomas, leukemias or sarcomas

What should I do before I have this medication?

Tell your health care team if you have or had significant medical condition(s), especially if you have / had:
- liver problems (such as hepatitis),
- kidney problems,
- or if you have any allergies.
Some methotrexate tablets contains a small amount of lactose. If you cannot have lactose, talk to your healthcare team.

Remember to:

Tell your health care team about all of the other medications you are taking.
Keep taking other medications that have been prescribed for you, unless you have been told not to by your health care team.

How will this medication affect sex, pregnancy and breastfeeding?

Talk to your health care team about:

How this medication may affect your sexual health.
Changes to your menstrual cycle (periods), if this applies to you.
How this medication may affect your ability to have a baby, if this applies to you.

This medication may harm an unborn baby. Tell your health care team if you or your partner are pregnant, become pregnant during treatment, or are breastfeeding.

If there is any chance of pregnancy happening, you and your partner together must use 2 effective forms of birth control at the same time until at least 6 months after your last dose. Talk to your health care team about which birth control options are best for you.
Do not breastfeed while on this medication.

How is this medication given?

Methotrexate may be given through an IV (injected into a vein), as IM (injected into muscle), or as a tablet (pill) you take by mouth. This will depend on what you are taking methotrexate for. Talk to your healthcare team about your treatment schedule.
If you missed your treatment appointment for methotrexate IV or IM, talk to your health care team to find out what to do.
If you are taking methotrexate oral tablets:
- Take these by mouth exactly as directed by your health care team. How often you take them will depend on your treatment schedule.
- Swallow whole with a glass of water on an empty stomach, at least 1 hour before or 2 hours after food.
- Avoid taking methotrexate tablets with milk products. They can make the drug not work as well.
- If you miss your dose, talk to your health care team to find out what to do.
- If you vomit (throw up) after taking your medication, talk to your health care team about what to do.
- If you take too much of your oral anticancer medication by accident, or if you think a child or a pet may have swallowed your medication, you must call the Ontario Poison Control Center right away at: 1-800-268-9017.

To Prevent or Treat Nausea and Vomiting

You may be given medications to help prevent nausea (feeling like throwing up) and vomiting (throwing up) before they start.

These are called anti-nausea medications and include medications such as ondansetron (Zofran®), granisetron (Kytril®), dexamethasone (Decadron®), prochlorperazine (Stemetil®), or others.

To Lower your Chance of Side Effects

If you are receiving high doses of methotrexate, you will also be given leucovorin (a type of vitamin) and fluids through an IV (injected into a vein) to reduce the side effects of methotrexate.
If you are given leucovorin, talk to your health are team about how and when to take this medication. See our leucovorin patient info sheet for more information.

What else do I need to know while on this medication?

Will this medication interact with other medications or natural health products?

This medication can interact with many other medications, vitamins, foods and natural health products. Interactions can make the treatment not work as well or cause severe side effects.
Tell your health care team about all of your:
- prescription and over-the-counter (non-prescription) medications and all other drugs, such as cannabis / marijuana (medical or recreational)
- natural health products such as vitamins, herbal teas, homeopathic medicines, and other supplements
Check with your health care team before starting or stopping any of them.
If you take seizure medications (such as phenytoin), your health care team may monitor your blood levels closely and may change your dose.
If you are taking a blood thinner (such as warfarin), your health care team may need extra blood tests and may change your dose.

What should I do if I feel unwell, have pain, a headache or a fever?

Always check your temperature to see if you have a fever before taking any medications for fever or pain (such as acetaminophen (Tylenol®)).
- Fever can be a sign of infection that may need treatment right away.
- If you take these medications before you check for fever, they may lower your temperature and you may not know you have an infection.

How to check for fever:

Keep a digital (electronic) thermometer at home and take your temperature if you feel hot or unwell (for example, chills, headache, mild pain).

You have a fever if your temperature taken in your mouth (oral temperature) is:
- 38.3°C (100.9°F) or higher at any time
  
  OR
- 38.0°C (100.4°F) or higher for at least one hour.

If you do have a fever:

Try to contact your health care team. If you are not able to talk to them for advice, you MUST get emergency medical help right away.
Ask your health care team for the Fever pamphlet for more information.

If you do not have a fever but have mild symptoms such as headache or mild pain:

Ask your health care team about the right medication for you. Acetaminophen (Tylenol®) is a safe choice for most people.
DO NOT take ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or ASA (Aspirin®), until you talk to your health care team as they may make your side effects worse.
Talk to your health care team if you already take low dose aspirin for a medical condition (such as a heart problem). It may still be safe to take.

What to DO while on this medication:

DO check with your health care team before getting any vaccinations, surgery, dental work or other medical procedures.
DO consider asking someone to drive you to and from the hospital on your treatment days.
DO tell your health care team about any serious infections that you have now or have had in the past.
DO protect your skin from the sun. Wear a long sleeved shirt, long pants and a hat. Apply sunscreen with UVA and UVB protection and an SPF of at least 30. Your skin may be more sensitive to the sun and you could develop a bad sunburn or rash more easily.
DO drink plenty of fluids (unless told differently) to prevent kidney problems. Drink at least 6 to 8 cups (2 Litres) of water or other liquids per day and urinate (pee) often., unless your healthcare team has told you to drink more or less.

What NOT to DO while on this medication:

DO NOT smoke or drink alcohol while on treatment without talking to your health care team first. Smoking and drinking can make side effects worse and make your treatment not work as well.
DO NOT drive, operate machinery or do any tasks that need you to be alert if you feel tired or dizzy.

How should I safely store this medication?

Oral tablets:

Store in the original packaging at room temperature, away from heat, light or moisture. Keep out of reach of children and pets.
Do not throw out any unused drugs at home. Bring them to your pharmacy for safe disposal.

How to safely touch oral anti-cancer medications

If you are a patient:

Wash your hands before and after touching your oral anti-cancer medication.
Swallow each pill whole. Do not crush or chew your pills.

If you are a caregiver:

Wear nitrile or latex gloves when touching tablets, capsules or liquids.
Wash your hands before putting on your gloves and after taking them off, even if your skin did not touch the oral anti-cancer medication.
Throw out your gloves after each use. Do not re-use gloves.
Do not touch oral anti-cancer medications if you are pregnant or breastfeeding.

What to do if oral anti-cancer medication gets on your skin or in your eyes

If medication gets on your skin:

Wash your skin with a lot of soap and water.
If your skin gets red or irritated, talk to your health care team.

If medication gets in your eyes:

Rinse your eyes with running water right away. Keep water flowing over your open eyes for at least 15 minutes.

What are the side effects of this medication?

The following table lists side effects that you may have when getting methotrexate. Methotrexate is usually given along with other medications to treat cancer; some of the side effects listed below may be due to those other medications. How likely you are to have a side effect will depend on your methotrexate dose.

The table is set up to list the most common side effects first and the least common last. It is unlikely that you will have all of the side effects listed and you may have some that are not listed.

Read over the side effect table so that you know what to look for and when to get help. Refer to this table if you experience any side effects while on methotrexate.

More Common Side Effects (10 or more out of 100 people)
Side effects and what to do	When to contact health care team
Nausea and vomiting What to look for? Nausea is feeling like you need to throw up. You may also feel light-headed. You may feel nausea within hours to days after your treatment. Nausea and vomiting are more likely to happen with high dose methotrexate. What to do? To help prevent nausea: It is easier to prevent nausea than to treat it once it happens. If you were given anti-nausea medication(s), take them as prescribed, even if you do not feel like throwing up. Drink clear liquids and have small meals. Get fresh air and rest. Do not eat spicy, fried foods or foods with a strong smell. Limit caffeine (like coffee, tea) and avoid alcohol. If you have nausea or vomiting: Take your rescue (as-needed) anti-nausea medication(s) as prescribed. Ask your health care team for the Nausea & Vomiting pamphlet for more information. Talk to your health care team if: nausea lasts more than 48 hours vomiting lasts more than 24 hours or if it is severe	Talk to your healthcare team if nausea lasts more than 48 hours or vomiting lasts more than 24 hours or if it is severe
Mouth sores (May be severe) What to look for? Round, painful, white or gray sores inside your mouth that can occur on the tongue, lips, gums, or inside your cheeks. In more severe cases they may make it hard to swallow, eat or brush your teeth. They may last for 3 days or longer. What to do? To help prevent mouth sores: Take care of your mouth by gently brushing and flossing regularly. Rinse your mouth often with a homemade mouthwash. To make a homemade mouthwash, mix 1 teaspoonful of baking soda and 1 teaspoonful of salt in 4 cups (1L) of water. Do not use store-bought mouthwashes, especially those with alcohol, because they may irritate your mouth. If you have mouth sores: Avoid hot, spicy, acidic, hard or crunchy foods. Your doctor may prescribe a special mouthwash to relieve mouth sores and prevent infection. Talk to your health care team as soon as you notice mouth or lip sores or if it hurts to eat, drink or swallow. Ask your health care team for the Oral Care (Mouth Care) pamphlet for more information.	Talk to your health care team as soon as you notice mouth or lip sores or if it hurts to eat, drink or swallow
Low appetite What to look for? Loss of interest in food or not feeling hungry. Weight loss. What to do? Try to eat your favourite foods. Eat small meals throughout the day. You may need to take meal supplements to help keep your weight up. Talk to your health care team if you have no appetite. Ask your health care team for the Loss of Appetite pamphlet for more information.	Talk to your health care team if it does not improve or if it is severe
Heartburn; stomach upset; bloating What to look for? Pain or burning in the middle or top part of your chest. It may get worse when you are lying down or bending over or when you swallow. A bitter or acidic taste in your mouth. What to do? Drink clear liquids and eat small meals. Do not eat acidic, fatty or spicy foods. Limit caffeine (like coffee, tea) and avoid alcohol. Avoid smoking or being around tobacco. Sit up or stand after eating. Do not lie down. Raise the head of your bed six to eight inches. You may need to use extra pillows to do this.	Talk to your health care team if it does not improve or if it is severe
Liver problems (May be severe) Your health care team may check your liver function with a blood test. The liver changes do not usually cause any symptoms. What to look for? Rarely, you may develop yellowish skin or eyes, unusually dark pee or pain on the right side of your belly. This may be severe. What to do? If you have any symptoms of liver problems, get emergency medical help right away.	Get emergency medical help right away

Other rare, but serious side effects are possible.
If you experience ANY of the following, speak to your cancer health care provider or get emergency medical help right away:

Bleeding from your gums, unusual nosebleeds, bruising easily or more than normal, or blood in your urine (pee) or stools (poo). If you have bleeding that doesn’t stop or is very heavy, you must get emergency help.
Signs of kidney problems such as lower back pain, swelling, pee less than usual and have weight gain that is not normal for you.
Signs of an allergic reaction such as rash, swollen lips, face or tongue, chest and throat tightness
Severe chest, belly , back or arm pain
Pain, swelling or hardening of a vein in your arm or leg
New cough, trouble breathing or coughing up blood
Feeling confused, trouble speaking or moving your arms or legs
Severe headache
New problems with balance, memory, difficulty with speaking or movements, personality changes
Any new changes to your vision
Severe muscle weakness, twitching
Seizures
Severe rash in areas where you have had radiation before
Severe rash, marks that may appear as “bulls-eyes”, may blister or peel, or appear together with swollen lymph glands
Red or purple patches on your skin or a rash that do not turn white when pressed

Who do I contact if I have questions or need help?

My cancer health care provider is: ______________________________________________

During the day I should contact:________________________________________________

Evenings, weekends and holidays:______________________________________________

Other Notes:

____________________________________________________________________________

For more links on how to manage your symptoms go to www.cancercareontario.ca/symptoms.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

methotrexate patient.pdf Info Sheet (French):

mthotrexate pour le patient.pdf Monograph:

methotrexate.pdf Funding Program: ODB - General Benefit Funding Instance:

methotrexate - oral tablets

Phonetic Spelling:

meth-oh-TREX-ate

Cancer Type: Breast Genitourinary Bladder / Urothelial Gynecologic Gestational Trophoblastic Disease Head and Neck Hematologic Leukemia - Acute Lymphoblastic (ALL) Leukemia - Acute Myeloid (AML) Leukemia - Acute Promyelocytic (APL) Lymphoma - Non-Hodgkin's High Grade Lymphoma - Non-Hodgkin's Intermediate Grade Lymphoma - Non-Hodgkin's Low Grade Lymphoma - T-cell Multiple Myeloma Sarcoma Desmoid Tumour Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Lundi, novembre 21, 2022 Universal Date: 2022-11-21 00:00:00 AddThis: Title URL: methotrexate Drug Display Status: Active Revision Summary:
Drug Monograph: Modified Pharmacokinetics, Indications, Adverse Effects, Dosage in renal impairment, Contraindications, Precautions, Pregnancy/lactation, Interactions and Monitoring sections