SYNONYM(S): Amethopterin, MTX

COMMON TRADE NAME(S): Rheumatrex®, Folex®(USA), Mexate®(USA)

CLASSIFICATION: Antimetabolite

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

MECHANISM OF ACTION: [1,2]

Methotrexate has been in clinical use since 1948. It 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 is cell cycle phase-specific (S phase).

PHARMACOKINETICS: [3,4,5,6,7,8,9,10,11,12,13,14,15,16]

Oral Absorption	well absorbed <30 mg/m², 20% >80 mg/m², bioavailability decreased by food and milk
Distribution	highest levels kidney, gallbladder, spleen, liver and skin, retained in liver for prolonged periods, crosses placenta, found in breast milk and malignant effusions
	cross blood brain barrier?	poorly
	Vd	0.4-0.8 L/kg, 16.4 L/m²
	PPB	50%
Metabolism	liver and intracellular metabolism to polyglutamated products
	active metabolite(s)	yes
	inactive metabolite(s)	yes
Excretion	excreted principally by the kidney (80%), biliary excretion <10%, significant inter- and intrapatient variability
	urine	60-100% excreted unchanged
	t½	1.5-3.5 hours
	t½	8-15 hours
	Cl	low dose: 36-138 mL/min/m² high dose: 24-100 mL/min/m² clearance higher in children than in adults

USES: [1,2,3,16,17]

SPECIAL PRECAUTIONS: [3]

Methotrexate powder is classified as dangerous goods under the Transportation of Dangerous Goods Act and must be declared as such for the purposes of transportation.

Methotrexate may be carcinogenic and has been reported to cause chromosome damage. Successful pregnancies have followed the use of methotrexate prior to conception. When administered to a pregnant woman, abortion is likely. It is excreted in breast milk in small concentrations and may accumulate in neonatal tissues, therefore, breast-feeding is not recommended.

SIDE EFFECTS: [3,18,19,20,21]

Dose-limiting side effects are underlined.
I = immediate (onset in hours to days); E = early (days to weeks);
D = delayed (weeks to months); L = late (months to years)

Incidence and severity of stomatitis varies with dose and schedule. Stomatitis is rare with weekly doses of 30mg/m², whereas doses of 20mg/m² on 5 consecutive days produce stomatitis in most patients. Risk factors for stomatitis include renal dysfunction, irradiation to head and neck area and prolonged infusion. Administration of leucovorin decreases the risk of toxicity to gastrointestinal tract.

Renal toxicity could be related to precipitation of methotrexate in the renal tubules and collecting ducts. Urinary methotrexate levels in excess of 1 mol/L exceed the solubility of methotrexate at pH 5.0 and promote drug precipitation. 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 >7.0). An example of a sodium bicarbonate regimen is 3 g IV q3h x 2 before, 50 mEq/L at 250 mL/h with and 50 mEq/L at 200 mL/hour for 48 hours after methotrexate.

Acute hepatic dysfunction (elevation of hepatic enzymes) may occur more frequently in patients receiving high-dose therapy and is reversible. Chronic hepatic fibrosis is more common in patients receiving long-term, low-dose therapy.

Due to the lower doses used, hepatic and renal toxicity is rare in breast cancer patients treated with methotrexate.

Clearance of methotrexate is delayed in the presence of fluid in the third space (eg, 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. 

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.

In active CNS leukemia, methotrexate clearance from the CNS may be delayed, possibly enhancing toxicity.

Chemical meningitis may occur with intrathecal methotrexate, beginning 2-4 hours after injection and lasting for 12-72 hours. This is characterized by stiff neck, headache, nausea and vomiting, fever and lethargy. The syndrome may be subacute or chronic, transient or permanent. Progression to spasticity, quadriplegia (transient or permanent), visual distrurbances and slurred speech can occur.

Other CNS toxicities include a acute encephalopathy consisting of aphasia or hemiparesis, occasionally with seizures, in patients receiving high-dose methotrexate (>200mg/kg IV or 8 g/m²).

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, 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. The immediate toxicity is associated with pulmonary edema and a syndrome of acute pleuritic chest pain. 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. Leucovorin administration does not appear to protect against pulmonary toxicity. Corticosteroids may hasten recovery.

INTERACTIONS [22,23,24,25,26,27,28,29,30]

SUPPLY AND STORAGE: [3]

Tablets
2.5 mg. The Lederle brand also contains cornstarch, magnesium stearate and lactose but is dye- and tartrazine-free. The David Bull Laboratories product contains no preservatives or colouring agents. Store at room temperature.

SOLUTION PREPARATION AND COMPATIBILITY: [3,31,32,33,34]

Injection
20 mg powder, 2.5 mg/mL solution (preservative-free), 10 mg/mL solution (preservative-free), and 25 mg/mL solution (preservative-free or preserved with benzyl alcohol). Store at room temperature, protected from light.

Reconstitute 20 mg powder with 2-10 mL NS, D5W or SWI to desired concentration.

For intrathecal administration, reconstitute 20 mg vial of powder with 10 or 20 mL preservative-free NS, Elliott's B solution or the patient's own spinal fluid to a final concentration of 2 or 1 mg/mL, respectively. Prepare immediately before use.

Reconstituted solution for injection
Stable at least 1 week at room temperature protected from light. However, the manufacturers recommend reconstitution immediately before use and that unused portions of vials reconstituted with preservative-free diluents be discarded. One manufacturer (DBL) recommends that their vials of preservative-free solution be punctured once only and unused portions discarded within 8 hours of puncture.

Stability in syringes
A 50 mg/mL solution is reportedly stable for at least 70 days at 25° C in plastic syringes. Cheung reported that mixtures of methotrexate 12 mg, cytarabine 30 or 50 mg, and hydrocortisone sodium succinate 15 or 25 mg in 12 mL of NS, D5W, Ringer's injection or lactated Ringer's were found to be physically compatible in disposable syringes at 25°C for at least 10 hours.

Diluted solution for infusion
Compatible for 7 days at room temperature in NS, D5W, D10W, dextrose-saline combinations, Ringer's Injection, lactated Ringer's, and 5% sodium bicarbonate. Solutions of 0.1 mg/mL are reported to undergo photodegradation (5-8% loss in 10 days, 11-17% in 20 days) on exposure to light. This effect was not noted in the more concentrated solutions.
Immersion of a needle with an aluminum component in methotrexate 25 mg/mL resulted in the formation of orange crystals on the aluminum surface after 36 hours at room temperature, protected from light.
Some mixtures with cytarabine, hydrocortisone sodium succinate, and sodium bicarbonate are compatible (see Stability in Syringes). Compatible with ondansetron. It is recommended that methotrexate not be mixed with other drugs. Incompatible with bleomycin, prednisolone sodium phosphate, ranitidine and some concentrations of heparin and metoclopramide.

PARENTERAL ADMINISTRATION: [2,35,36,37]

DOSAGE GUIDELINES: [17,22,35,36,37,38,39,40]

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 white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.

Adults:

Oral:
     daily: 0.625-2.5 mg/kg
     q1-2w: 15-30 mg x 5 days (or IM)
     biw (twice a week): 10-15 mg/m²/dose (or IM)
     q2w: 2.5 mg/kg
     daily: 3.3 mg/m² x 4-6 weeks

Intravenous:
     q1w: 25-40 mg/m²
     q1-3w: 100 mg-30 g/m² followed by leucovorin
      rescue within 2-24 hours

Intrathecal:
q4-7d: 12 mg in 6 mL preservative-free NS
Dose is the same whether given intrathecally or into an Ommaya (intraventricular) reservoir. Elderly patients may require a reduced dose.

Leucovorin rescue:
See leucovorin monograph for dosing guidelines for leucovorin rescue.

Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression".

Dosage in renal failure:	CrCl (mL/sec)	or	Serum Cr (mol/L)	% usual dose
	0.2-0.8		100-180	50%
	<0.2		>180	omit
Dosage in hepatic failure:	Bilirubin (mol/L)	% usual dose
	50-85	75%
	>85	omit

Children:

Oral:
     q1w: 15-20 mg/m²

Intravenous:
     q4w: 300-3000 mg/m²
     q3-4w: 8-12 g/m² IV (top dose 20 g)
         with hydration of 3 L/m²/day, alkalinization of urine and leucovorin
         rescue; use only preservative-free methotrexate
      6 g/m² loading dose, followed by 1.2 g/m²/hour x 23 hours with
        leucovorin rescue starting 12 hours after end of methotrexate infusion:
        200 mg/m² loading dose, followed by 12 mg/m² q3h x 6 doses, then
        q6h until methotrexate levels fall below 0.1 mol; use preservative-free
        methotrexate

Intrathecal:

     Dose of methotrexate is the same whether it is given intrathecally or into
     an Ommaya (intraventricular) reservoir.

METHOTREXATE FACT SHEET
FOR THE HEALTH CARE PROFESSIONAL

Notes:

• High dose methotrexate:     
  • Do not administer high dose methotrexate until leucovorin rescue is available on the unit.        
  • With doses >1 g/m², an alkaline urine and high urine output must be maintained to prevent precipitation of methotrexate in the renal tubules. 
• Leucovorin rescue:     
  • Give leucovorin starting 24 hours after methotrexate or as described in protocol.  
  • Repeat dose if patient vomits after oral administration and tablets are visible in vomitus.  
  • Use parenteral route for doses greater than 25 mg or if patient unable to tolerate oral.  
  • Methotrexate serum levels can be used to adjust leucovorin rescue doses. 
• Methotrexate powder must be declared as dangerous goods when shipped.

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Cancer Drug Manual^© 1994