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Drug Monographs
Treatment Regimens

Scientific Name:
METHOTREXATE IV (see also Methotrexate High Dose, Methotrexate Intrathecal)
Brand Name(s):
Amethopterin®, Methotrexate®

Drug Monograph

Pharmacology

Mechanism of Action

Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthase, resulting in inhibition of purine and thymidylic acid synthesis. It is cell cycle specific for the S phase of the cycle.

Pharmacokinetics

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:
<10% of dose is metabolized, converted to 4-deoxy-4-amino-N10-methyl pteroic acid (DAMPA) by carboxypeptidase (GI-tract), to 7-hydroxymethotrexate by aldehyde oxidase (liver) and polyglutamated intracellularly
metabolite(s): active- yes inactive- yes
Excretion:
excreted principally by the kidney (80%) via both glomerular filtration and active transport, biliary excretion <10%, significant inter- and intrapatient variability; small amounts are excreted in the feces
Urine: 44%-100% excreted unchanged
Cl:  low dose: 36-138 mL/min/m2; clearance higher in children than in adults
t½ a  low doses: 3-10 hours
t½ b 8-15 hours

Side Effects

IMMEDIATE ONSET (hours to days)
* anaphylaxis (rare)
   nausea and vomiting (dose related, 40% with high dose)
   radiation recall reaction (rare)
   tumour lysis syndrome- rare
EARLY ONSET  (days to weeks)
* myelosuppression, leukopenia, neutropenia- nadir 7-14 days, recovery 14-21 days)- anemia, thrombocytopenia,
   stomatitis (dose related,), diarrhea, anorexia
   malaise, fatigue, chills and fever, dizziness
* gastrointestinal bleeding, perforation, pancreatitis
   dizziness, drowsiness, dysphagia
   elevated liver function tests
   skin problems (pigmentation changes, photosensitivity, erythematous rashes, pruritus)
* toxic epidermal necrolysis (Lyell’s Syndrome), Stevens-Johnson Syndrome
   anorexia
   alopecia (usually mild)
* lung problems- obstructive pulmonary disease, interstitial pneumonitis
   eye problems (conjunctivitis, blurred vision, visual changes, transient blindness/vision loss)
* kidney problems: toxic nephropathy (with high doses), renal failure
* cardiovascular problems- pericarditis/pericardial effusion (damage to heart, rare)
   hypotension
   thrombosis
   arthralgia/myalgia- rare
   osteoporosis- rare,
DELAYED/LATE ONSET (weeks to years)
* hepatotoxicity (fibrosis, cirrhosis, interstitial pneumonitis)
   central nervous system problems  (acute encephalopathy, paresthesia)
   infertility
   carcinogenicity- rare

Therapeutics

Approved Indications

• Acute lymphocytic leukemia
• Choriocarcinoma
• Graft versus host disease (prophylaxis)
• Mycosis fungoides
• Non-Hodgkin’s lymphoma

OTHER ONCOLOGY USES (Not Approved)
• Breast cancer
• Bladder cancer       
• Chorioadenoma destruens and hydatidiform mole
• Head and neck cancer 
• Lung cancer     
• Meningeal leukemia
• Osteogenic sarcoma
• Sarcoma, adult soft tissue
• Prevention of acute graft-versus host disease

Routes

• Oral (well absorbed <30 mg/m2)
• Intramuscular (rotate sites)
• Direct IV (low doses 25-40 mg/m2/week)
• Intermittent IV (in appropriate volume over 1-8 hours)
• Continuous IV (in appropriate volume over 24 hours)

Administration

• Doses <100mg may be given by slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline) over 1-2 minutes; may give by push over 15 minutes for larger doses (eg. 100-300mg) (administering nurse should be certified to administer IV push chemotherapy agents)
• May be given by IM or direct IV push, followed by a Normal Saline IV flush, if no IV line has been set up
• Larger doses (eg. >100mg) may be followed by Leucovorin rescue 24 hours later
• Doses from 100-200mg may be mixed in 100mL minibag (5% Dextrose, Normal Saline); Infuse over 30 (to 60) minutes
• Doses from 200-500mg may be mixed in 250-500mL bag (5% Dextrose, Normal Saline); Infuse over 30 (to 120) minutes
• Doses from >500mg may be mixed in 500mL bag (5% Dextrose, Normal Saline); Infuse over 1 (to 4) hour(s)

IV Compatibility

Normal saline, dextrose 5%, lactated Ringer’s.

Dosing

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
• 1 mg/kg IM/IV days 1, 3, 5, 7 (with leucovorin calcium 10% of MTX dose IM days 2, 4, 6, 8)- Gestational trophoblastic disease
• 0.4 mg/kg/day IV daily for 5 days- Gestational trophoblastic disease
• 15mg/m2 (IBSA) on Day +1 and 10 mg/m2 on days +3, +6, and +11- BMT graft-versus-host-disease prophylaxis
• q4w: 40 mg/m² days 1 and 8
• q4w: 30 mg/m2 days 1, 15 and 22
• 220 mg/m2 IV bolus followed by 60 mg/m2/hour x 36 hours by continuous IV infusion - Acute lymphoblastic leukemia

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

Pediatric
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 0.1µmol; use preservative-free methotrexate

Dose Adjustment Criteria

Hepatic dysfunction
Reduce to 75% dose if Bili = 50-85µmol/L or AST> 180IU/L;
Omit if Bili > 85µmol/L
Renal failure
Reduce to 50% dose if CrCl = 0.2-0.8mL/sec or Serum Creatinine= 100-180µmol/L; Omit if CrCl < 0.2mL/sec or Serum Creatinine >180µmol/L (Suggested action)

Antiemetic Risk

LOW RISK (Less than 10% of patients)
• No routine antiemetic pre-chemotherapy or post-chemotherapy

Contraindications

• Pregnancy and breast feeding • Low WBC, RBC, platelets (myelosuppression) • Effusions • Severe renal failure

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Clinical assessment of stomatitis; oral examination upon patient complaint of a sore mouth
• Baseline renal function tests (if failure suspected) [serum creatinine, electrolytes & BUN]

SUGGESTED CRITERIA
• Baseline and periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels (serum proteins may be added if indicated)]
• Baseline and periodic chest X-ray

Extravasation Hazard

Minimal

Significant Interactions

* Drinking alcohol while taking Methotrexate increases hepatotoxicity and should be avoided. • Acitretin: may increase hepatotoxicity of Methotrexate (avoid combination) • Alitretinoin (systemic): may increase hepatotoxicity of Methotrexate • BCG: Methotrexate may decrease therapeutic effect of BCG (avoid combination) • Bile acid sequestrants: may decrease absorption of Methotrexate • Ciprofloxacin (systemic): may increase the serum concentration of Methotrexate • CloZAPine: Methotrexate may enhance the toxicity of CloZAPine, especially agranulocytosis. (avoid combination) • Cyclosporine (systemic): may increase the serum concentration of Methotrexate. This may cause vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Methotrexate may increase the serum concentration of Cyclosporine. This may result in nephrotoxicity. (consider therapy modification) • Denosumab: may enhance the toxicity of Methotrexate, especially the risk for serious infections • Digoxin: Methotrexate may decrease absorption of Digoxin. • Echinacea: may diminish the therapeutic effect of Methotrexate, because Echinacea may stimulate the immune system. Do not take Echinacea. • Eltrombopag: may increase the serum concentration of OATP1B1/SLCO1B1 substrates. Consideration of a preventative dose reduction may be warranted. (Consider therapy modification) • Leflunomide: Methotrexate may increase the toxicity of Leflunomide, especially the risk of pancytopenia and/or hepatotoxicity • Loop diuretics (e.g. furosemide): Methotrexate may diminish the therapeutic effect of loop diuretics. Methotrexate may increase the serum concentration of these drugs. Loop diuretics may also increase the serum concentration of Methotrexate. Monitor for increased Methotrexate and/or loop diuretic levels/toxicity and monitor for decrease therapeutic effect of loop diuretic. Dose reductions may be needed. • NSAIDs: may increase the serum concentration of Methotrexate (Consider therapy modification) • Penicillins: may increase the serum concentration of Methotrexate • P-glycoprotein/ABCB1 Inducers: may decrease the serum concentration of P-glycoprotein substrates, and may also limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large quantities (brain, T cells, testes, etc.) • P-glycoprotein/ABCB1 Inhibitors: may increase the serum concentration of P-glycoprotein/ABCB1 substrates. P-glycoprotein inhibitors may also increase the distribution of p-glycoprotein substrates to specific cells, tissues, or organs where p-glycoprotein is found in large amounts. • Phenytoin, Fosphenytoin: Methotrexate may decrease the serum concentration of Fosphenytoin-Phenytoin • Probenecid: may increase serum concentration of Methotrexate (Avoid combination if possible, and consider lower Methotrexate doses/monitor for toxicity if used concomitantly.) • Proton Pump Inhibitors: may increase serum concentration of Methotrexate • Roflumilast: may increase immunosuppressive effect of Methotrexate (Consider therapy modification) • Salicylates: may increase serum concentration of Methotrexate. Doses used for prophylaxos of cardiovascular events are not likely of concern. • Sapropterin: Methotrexate may decrease serum concentration of Sapropterin (may decrease tissue concentrations of tetrahydrobiopterin. • SulfaSALAzine: may increase hepatotoxicity of Methotrexate • Sulfonamide antibiotics: may increase the toxicity of Methotrexate. Consider avoiding concomitant use of Methotrexate and either sulfamethoxazole or trimethoprim. If used together, monitor for Methotrexate toxicity (e.g. bone marrow suppression). • Tacrolimus (topical): may increase toxicity of Methotrexate (avoid combination) • Theophylline derivatives: Methotrexate may increase serum concentration of these drugs • Trastuzumab: may increase the neutropenic effect of Methotrexate • Vaccines (inactivated): Methotrexate may diminish the effect of vaccines • Vaccines (live): Methotrexate may increase the toxicity of live vaccinations • Vitamin supplements containing folic acid: may decrease Methotrexate levels (avoid combination) • Vitamin K Antagonists (e.g. Warfarin): Methotrexate may increase/decrease the anticoagulant effect of these drugs.

Product Information

Commercial Product Description

Yellow tablets with 2.5mg Methotrexate. Generic products available Multidose vials with 50mg/2mL, 500mg/20mL, 1000mg/40mL, 5000mg/200mL. Also known as Amethopterin. For intrathecal use: Vials of 20mg for reconstitution,Vials of 20mg/2mL unpreserved solution.

Pharmaceutical Considerations

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.

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.

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.

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.

Handling Risk Level

Pregnancy DKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D

  • This drug must be handled using precuations outlined in CCNS Policies for Occupational Safety and Administering Cancer Chemotherapy

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status - Injection- Basic Level for low dose • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Formulary • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.



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