Trainee’s Guide to Methotrexate

Publication: 30/09/2020  
Next review: 30/09/2023  
Clinical Guideline
CURRENT 
ID: 6670 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2020  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Trainee’s Guide to Methotrexate

Guidance for the Administration and Monitoring Requirements for High Dose Methotrexate within Adult Oncology (includes TYA; excludes trial patients).

Methotrexate Mechanism of Action

High dose methotrexate, defined as ≥500mg/m2 (1), is given in combination with doxorubicin and a platinum agent in most osteosarcoma protocols. Methotrexate dose for osteosarcoma patients is 12g/m2 given by 4 hour intravenous infusion followed by a two to three day period of regular leucovorin (folinic acid), known as ‘rescue’ doses until methotrexate is cleared.

Methotrexate is an anti-metabolite that interferes with the metabolism of folic acid. After entry into the cell, methotrexate is polyglutamated, binds dihydrofolate reductase (DHFR) with an affinity 1,000-fold greater than that of folate, and competitively inhibits the conversion of dihydrofolate to tetrahydrofolate (2). Tetrahydrofolate is essential for biosynthesis of thymidine and purines, which are needed for synthesis of DNA. Blockade of tetrahydrofolate synthesis by methotrexate leads to the inability of cells to divide and to produce proteins.

The requirement to use high dose methotrexate in osteosarcoma compared to conventional dose methotrexate may be explained by an intrinsic resistance of osteosarcoma to transport the drug across the cell membrane. Potential mechanisms of resistance include decreased transport through the reduced folate carrier (RFC) and increased expression of DHFR due to DHFR gene amplification and/or overexpression (3). This is particularly evident in metastatic or recurrent tumours.

The doses of methotrexate needed to achieve high plasma concentrations in osteosarcoma patients MUST be followed by leucovorin rescue to prevent increased toxicity to normal tissues.

Leucovorin is a derivative of tetrahydrofolate which does not require DHFR activation so can block the effects of methotrexate when given after.

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Adverse Effects of Methotrexate

  • Blood & bone marrow
    • Myelosuppression
  • Renal
    • Nephrotoxicity - reversible or irreversible
  • Gastrointestinal
    • Mucositis
    • Nausea and vomiting
    • Diarrhoea
  • Hepatic
    • Acute transaminitis (transient in nature and typically resolves spontaneously)
  • Dermatology
    • Maculopapular rash
    • Skin hyperpigmentation
    • Photosensitivity
  • Neurology
    • Headaches
    • Encephalopathy
  • Respiratory
    • Interstitial pneumonitis (rare)

Please refer to SPC for complete list of side effects.

 

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Things to Consider Prior to Methotrexate Administration

Line access

A double lumen central line should be in place before commencing high dose methotrexate to safely administer sodium bicarbonate 8.4% solution concurrently with pre and post hydration fluids.

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Concurrent medication

Drug interactions with methotrexate can significantly increase toxicity. The list below is not exhaustive so check all drug interactions carefully. The most common/serious interactions are:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. diclofenac, ibuprofen, aspirin etc.
  • Penicillins (should be stopped at least 48 hours before methotrexate administration and avoided until methotrexate has been cleared)
  • Co-trimoxazole and other sulphonamides e.g. trimethoprim (should be stopped 5-7 days before methotrexate administration)
  • Proton pump inhibitors (PPIs) e.g. lansoprazole, omeprazole (these can be continued during the methotrexate cycle if the patient has requirement for a PPI, however, this prescription should be reviewed in the event of excess toxicity or raised serum methotrexate levels)

**Annotate the allergy section of the eMeds chart to remind others to avoid these drugs**

Nephrotoxic medicines (e.g. gentamicin, vancomycin) should be withheld or substituted where possible until methotrexate is cleared.

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Excess fluid space e.g. pleural effusion or ascites

Methotrexate can accumulate in fluid and cause prolonged excretion with increased toxicity. In patients with significant third space fluid accumulation, consideration should be given to drainage prior to commencing high dose methotrexate. Methotrexate can be given in such cases under consultant request but close attention must be paid to serum methotrexate levels with regular review for toxicity. Also be alert to any development of fluid accumulation during treatment with close attention to fluid balance +/- body weight.

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Mucosal toxicity

Any mucosal toxicity from previous chemotherapy cycles should have resolved to ≤ grade 1 (ulceration/inflammation of the oral mucosa which is asymptomatic or with mild symptoms whereby intervention is not indicated) before methotrexate administration. If there has been severe mucositis (grade 3/4) with or without other toxicities from previous doses of methotrexate, higher doses of folinic acid rescue or more prolonged courses of this may be needed. This needs to be discussed with the treating registrar or consultant.

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Full blood count

Neutrophils

≥ 0.25 x109/L

Platelets

≥ 50 x109/L

It is important to consider the general clinical condition of the patient and risk of neutropenic sepsis prior to treatment. If blood count thresholds are not reached, a delay until recovery is preferred, rather than dose modifications to maintain dose intensity over the full course.

Delay blood transfusions until methotrexate cleared (can alter pH and cause electrolyte imbalances); only transfuse if the patient is markedly symptomatic.

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Liver function tests

ALT

<10xULN

Bilirubin

<27 µmol/L

(Providing an absence of other causes of liver dysfunction; to discuss with treating team if results outside above parameters)

It is expected that patients receiving high dose methotrexate will develop hypertransaminasemia and occasionally hyperbilirubinemia. These elevations can last up to two weeks following methotrexate infusion and would not be considered toxicity requiring discontinuation or dose alteration.

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Renal function

Creatinine clearance before starting methotrexate should be >70 ml/min. 

If creatinine clearance <70ml/min, treatment with methotrexate needs to be discussed with the consultant.

Renal function requires monitoring with DTPA GFR (via nuclear medicine) prior to the first methotrexate dose and then after every 4 doses.

 

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Hydration fluids

Pre and post hydration fluids containing glucose 4%, sodium chloride 0.18% and potassium chloride 20mmol/L are prescribed on the chemotherapy prescription for administration and commence early morning (3am) to allow for methotrexate administration before 12noon. Methotrexate regimens include approximately 4L a day to ensure good hydration and urine output.

If diuresis is not established or urine output falls to <100ml/hour before starting methotrexate then the rate of IV fluids should be increased. This needs to be discussed with the treating registrar or consultant.

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Urine pH

This should be >7 before commencing methotrexate and until methotrexate levels fall to <0.2 micromol (μmol)/L.

The establishment of an alkaline diuresis during treatment is important to increase the solubility of methotrexate and its 7-hydroxy metabolite and prevent nephrotoxicity resulting from precipitation of these substances in the renal tubules.

Alkalinisation of urine can be achieved by using sodium bicarbonate 8.4%. This is started 8 hours before starting the methotrexate infusion and run alongside the hydration fluids. Urine pH should be monitored when the patient produces urine (usually every 2-4 hours). It may be necessary to increase the rate of the sodium bicarbonate 8.4% infusion to maintain alkaline urine (pH 7-8).

An alternative way of alkalinising the urine is to use oral acetazolamide 500mg capsules QDS starting 24 hours prior to the methotrexate and continuing for 72 hours after.

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Things to Consider During Methotrexate Administration

Lab tests

FBC, U&Es and LFTs should be measured daily. Twice daily samples may be necessary if any concerns with delayed methotrexate clearance. Methotrexate levels should also be measured daily; see information below for full details.
Body weight, strict fluid balance, urine pH and observations should also be monitored daily.

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Chemotherapy induced nausea and vomiting (CINV)

Methotrexate ≥500mg/m2 is considered highly emetogenic (5) although emesis can generally be managed with metoclopramide and if necessary a 5-HT3 receptor antagonist such as ondansetron.

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Mucositis

Mucositis is common and can be managed as per the Leeds Teaching Hospitals Trust guidance on Leeds Health Pathway.

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Folinic acid/Leucovorin rescue

Intravenous (IV) folinic acid (leucovorin) is commenced 24 hours after the start of the methotrexate infusion at a dose of 15mg/m2 every 6 hours and this treatment is continued until plasma methotrexate levels have fallen <0.2 μmol/L.

Folinic acid is prescribed on the chemotherapy prescription for nursing administration.

Note: Oral doses of folinic acid can reverse methotrexate toxicity successfully, however they are not used often in practice. This is because doses >25mg have significantly reduced oral bioavailability so IV administration is preferred (6).

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Interpreting Methotrexate Levels and Adjusting Folinic Acid Rescue

Levels will be checked every 24 hours, starting 24 hours after the start of the methotrexate infusion until the drug is excreted. Table content is taken from the EURAMOS-1 protocol (7).

The upper limit of serum methotrexate:

 

at 24 hours

20μmol/L

at 48 hours

2μmol/L

at 72 hours

0.2μmol/L

Once the level is <0.2μmol/L, the patient can be discharged home (providing no other issues).

If the level is higher than the upper limit of normal at a particular time point, the folinic acid dose will need to be increased for the next 24 hours (or 4 doses), after which, a repeat methotrexate level will be checked and the folinic acid dose re-reviewed.

The dosing interval for folinic acid has been derived empirically; the half-life of the primary active metabolite is approximately 6 hours. The benefit of dosing every 3-4 hours compared with every 6 hours has not been proven, although mean plasma levels are 2-3 times higher with every 3 hour administration [1] so may be beneficial for the management of severe toxicity (i.e. grade 3/4 mucositis, creatinine rises >100%) following delayed methotrexate clearance. This needs to be discussed with the treating registrar or consultant.

Calculation for leucovorin (folinic acid) dose adjustment taken from the EURAMOS-1 protocol (7).

 

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Raised Serum Methotrexate Level with Nephrotoxicity

Delayed clearance of methotrexate can cause severe life-threatening bone marrow and gastrointestinal complications after an early acute kidney injury. It will be seen if there is a rise in creatinine >100% within 24 hours of methotrexate. Severe vomiting, diarrhoea and experiencing yellow vision during or shortly after the administration of methotrexate can be indicative of methotrexate toxicity.

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Management

  • Continued hydration/IV fluids containing glucose 4%, sodium chloride 0.18% and potassium chloride 20mmol/L with careful monitoring of potassium depending on renal function
  • Continued alkalinisation of urine using sodium bicarbonate 8.4% solution
  • The minimum diuresis should be increased to 600ml/m2/6hrs
  • Increase the dose of folinic acid (leucovorin) as per the calculation above
  • Optimise renal function by review of medications and discussion with renal team on-call in case emergency electrolyte balance issues emerge
  • Glucarpidase administration may need to be considered and discussed with the treating consultant and specialist pharmacist (on-call if out of hours).

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Glucarpidase

Glucarpidase (Carboxypeptidase G2, Voraxaze™) is an effective agent for the treatment of severe or life-threatening methotrexate-induced toxicity.

Glucarpidase is a recombinant form of the bacterial enzyme carboxypeptidase G2. It hydrolyses the carboxyl terminal of methotrexate to form inactive metabolites, 4-deoxy-4amino-N-methylpteroic acid (DAMPA) and glutamate. This allows elimination of methotrexate via a non-renal route.

Glucarpidase is an unlicensed treatment for adults and children receiving high dose methotrexate who develop a significant deterioration in renal function with toxic plasma methotrexate levels. A significant deterioration in renal function is regarded as a serum creatinine that is at least 1.5 times the upper limit of normal and rising, or the presence of oliguria.

Before using glucarpidase, all other supportive measures must have been optimised, such as the use of fluids and folinic acid. Glucarpidase can only be used under consultant request and is only available through application on a named patient basis.

Dose= 50units/kg as single IV bolus over 5 minutes (8)

Do not administer folinic acid within 2 hours before or after a dose of glucarpidase (folinic acid is a substrate for glucarpidase). Continue to administer folinic acid rescue after glucarpidase. For the first 48 hours after glucarpidase, continue administering the same folinic acid rescue dose as prior to glucarpidase (8).

Serum methotrexate levels are unreliable within 48 hours following administration of glucarpidase. DAMPA interferes with assays resulting in erroneous measurement and overestimation of the methotrexate level.

Beyond 48 hours, administer folinic acid rescue based on measured methotrexate levels. Folinic acid should be continued until the methotrexate concentration has been maintained below the treatment threshold (methotrexate level < 0.2μmol/L) for a minimum of 3 days with continued hydration and alkalinisation of the urine (8).

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Provenance

Record: 6670
Objective:
Clinical condition:
Target patient group:
Target professional group(s): Pharmacists
Secondary Care Doctors
Adapted from:

Evidence base

1. Ann, S., LaCasce, MD. 2020. Therapeutic use and toxicity of high dose Methotrexate. [Online]. [Accessed 28th June 2020]. Available from: https://www.uptodate.com/contents/therapeutic-use-and-toxicity-of-high-dose-Methotrexate

2. Howard, S.C., McCormick, J., Pui, Ching-Hon et al. 2016. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist. 21 (12), pp. 1471-1482

3. Guo, W., Healey, J.P., et al. 1999. Mechanisms of Methotrexate Resistance in Osteosarcoma. Clin Cancer Res. (3), pp. 621-627. Available from: https://clincancerres.aacrjournals.org/content/5/3/621.full-text.pdf

4. Accord Healthcare Limited. 2020. Summary of Product Characteristics: Methotrexate 25mg/ml solution for injection. [Online].  Middlesex. Accord Healthcare Ltd. [Accessed 28th June 2020]. Available from: https://www.medicines.org.uk/emc/product/4281/smpc

5. Leeds Teaching Hospitals NHS Trust. 2018. Anti-Emetic Guidelines for Adults Receiving Chemotherapy and Radiotherapy. [Online]. [Accessed 1st July 2020]. Available from: http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=1491

6. McGuire, B.W., Haynes, J.D., et al. 1987. Absorption kinetics of orally administered leucovorin calcium. NCI Monogr. (5), pp. 47-56

7. EURAMOS-1 protocol. 2015. A randomized trial of the European and American Osteosarcoma Study Group to optimize treatment strategies for resectable osteosarcoma based on histological response to pre-operative chemotherapy

8. VORAXAZE full prescribing information: Available from: https://voraxaze.com/Voraxaze/media/VRX/pdf/VORAXAZE-PI_August-2019_2-column-format.pdf

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Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

Resources

If you are unsure, ask a registrar who has done the sarcoma post recently, the consultant or pharmacist on-call. Alternatively, the registrar(s) and pharmacist covering the sarcoma team are usually happy to help!

For pharmacists:

NHS England Clinical Commissioning Policy link for glucarpidase below for further information: https://www.england.nhs.uk/wp-content/uploads/2018/07/Glucarpidase-for-the-urgent-treatment-of-Methotrexate-induced-renal-dysfunction.pdf

H:\Cluster C Leeds Cancer Centre\TYA, Sarcoma, Germ cell protocols\Methotrexate - contains further information about glucarpidase and how to access it.

Useful information is available in the EURAMOS protocol. Appendix A contains information surrounding the management of methotrexate toxicity and delayed methotrexate excretion.

H:\Cluster C Leeds Cancer Centre\TYA, Sarcoma, Germ cell protocols\Osteosarcoma\Oncology Information

Leeds Health Pathways (LHP) Oral mucositis guidelines: http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=3124

 

For registrars:

NHS England Clinical Commissioning Policy link for glucarpidase below for further information: https://www.england.nhs.uk/wp-content/uploads/2018/07/Glucarpidase-for-the-urgent-treatment-of-Methotrexate-induced-renal-dysfunction.pdf

Trials protocols and guidelines on Methotrexate can be found in the Oncology L Drive in the Sarcoma folder (L:\Sarcoma\Methotrexate Level Interpretation & Management).

Glucarpidase information can be found in the Sarcoma L-drive folder - this includes the commissioning statement on the use of glucarpidase, out-of-hours protocol on ordering and administration of glucarpidase and the patient access form (which will need to be completed to enable administration).

Leeds Health Pathways (LHP) Oral mucositis guidelines: http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=3124

 

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