Fluorouracil is commonly used alone or in combination for treating solid tumours. It is usually dosed at its maximum tolerated dose via intravenous injection or infusion. Mild toxicities to life-threatening events may occur with fluorouracil administration at greater than the intended dose or dose interval. This may occur due to errors in infusion pump programming, dose miscalculations, or device malfunction. There is currently no standard definition of fluorouracil infusion overdose. Toxicities can include but are not limited to myelosuppression, mucositis, diarrhea, nausea/vomiting, esophagitis and gastritis 2. Less common but potentially severe events can include cardiogenic shock, gastrointestinal bleeding and perforation 3. For further information on fluorouracil, please refer to AHS Provincial Parenteral Monograph on Fluorouracil and/or the BCCA Parental Drug Information guide.
Fluorouracil infusions may be prescribed to infuse over multiple days at home via an ambulatory Infusor pump. In Cancer Care Alberta (CCA), Baxter Elastomeric Infusors are utilized. These Infusors are non-electronic medication pumps whereby medication is delivered to the patient as the elastomeric "balloon" consistently and gently pushes solution through the IV tubing and into the catheter/port. The Infusors are available in a variety of volumes and flow rates and flow within +/-10% of the labelled flow rate. In addition, various environmental factors can affect the accuracy of flow rate parameters as outlined below. It is important to note that there is this expected variation in flow rate accuracy and this guideline is intended to address situations where there has been an unanticipated significant variation in the expected flow rate.
To ensure an accurate flow rate, the access system should be 22 gauge or larger when using an Infusor.

# Fill volume
Infusor flow rate is most accurate when filled to the labelled nominal volume. Infusors flow faster than labelled flow rate if UNDERFILLED (filled to < 81% of optimal fill volume).
Note: CCA pharmacy prepares Infusors to nominal fill volume.
Pump Height Flow rate is most accurate when the balloon reservoir and the Luer Lock connector are at the same height. Flow rate can decrease ~ 0.5% per 2.5 cm if the balloon reservoir is below the Luer Lock connector. Flow rate can increase ~ 0.5% per 2.5 cm if the balloon reservoir is above the Luer Lock connector.

# Guideline Resource Unit
Prescribing medical staff, pharmacy and nursing must follow procedures to minimize the risk of an error in dose calculation or incorrect selection of the Baxter Elastomeric Infusors device. In the event of a fluorouracil overdose/overinfusion, appropriate and timely measures should be implemented per the recommendations outlined below.
Guideline Question 1. What is the recommended management strategy for a potential overdose of fluorouracil infusion?

# Search Strategy
This guideline was originally developed in 2016 to ensure the safe management of a fluorouracil infusion overdose for patients in Alberta. A literature review was conducted in July, 2022 and did not result in any major updates. The guideline was originally adapted from the 2015 BC Cancer Agency (BCCA) Cancer Management Guideline: Management of 5-fluorouracil (5FU) infusion overdose at the BCCA 1 (Interim Guidance).

# Target Population
This guideline applies to adult patients with cancer who are being treated with fluorouracil. Recommendations 1. The BCCA defines a fluorouracil Infusor overdose as administration of fluorouracil via Infusor at  2 times the intended rate with completed delivery of greater than 50% of the intended total fluorouracil dose. As per manufacturer's instructions, an overdose can be determined by visual inspection 4   o Clinical assessment every 1-2 days for 7 days then as required.
- Labs every 1-2 days for 7 days then as required: CBC, electrolytes, LFTs and creatinine monitoring. - If on combined modality therapy -notify responsible Radiation Oncologist and hold radiation therapy, be aware if pelvic irradiation is underway that myelosuppresion may be worse than what would be expected by fluorouracil alone. - Consider contacting PADIS for additional information.
- Inform administration, medical, nursing and pharmacy leadership of the patient event.
If the overdose rate is greater than 10X intended rate (with completed delivery of greater than 50% of the intended total fluorouracil dose):
- Patient should be hospitalized for monitoring and supportive management including assessment of hemodynamic status and intravenous hydration. 4 - Obtain a baseline ECG.
- Daily CBC, electrolytes, LFTs, creatinine.
- Discontinue concomitant medications which may impair clearance of fluorouracil: cimetidine, metronidazole, and thiazide diuretics. 6 - Initiate filgrastim (G-CSF) at a dose of 5 mcg/kg sc daily 24 hours after disconnecting the pump and continuing for a minimum of 7 days or until past nadir to ANC > 1.0. 3,5 - Start the patient on broad spectrum antibiotic prophylaxis.
- Initiate glutamine 18 g PO daily for prevention of fluorouracil intestinal toxicity. 7,8 - Administration of uridine triacetate (Vistongard, Wellstat) is strongly advised: 9 Guideline Resource Unit o Uridine triacetate is an oral prodrug of uridine, a specific pharmacologic antidote for fluorouracil poisoning. o It is recommended that treatment with uridine triacetate should commence as soon as possible (8-96 hours) after a suspected severe fluorouracil overdose. 6 o See Appendix B for detailed instructions for obtaining uridine triacetate. o Dosing regimen from Wellstat Therapeutics: 10  Adults ( 18 years): One sachet or orange-flavored coated granules (contains 10 g of uridine triacetate/dose) taken every six hours for a total of 20 doses. It is recommended that granules be mixed with applesauce, pudding, yogurt, or similar food to make the ingestion easier and followed by 8 ounces of water. The first dose is to be taken as soon as possible after the fluorouracil overdose has occurred but not less than 3 hours according to the manufacturer due to potential interference with fluorouracil renal clearance. If the patient vomits within 2 hours of administration of uridine triacetate the dose can and should be repeated.  Consider ondansetron 8 mg po 20 minutes before each dose of uridine triacetate to prevent nausea and vomiting 11. It is reasonable to administer up to 32 mg of ondansetron/day in split doses in the absence of significant electrolyte abnormalities in magnesium or potassium of a history of long QT syndrome. - Initiate fluoroquinolones in the event of diarrhea if not already initiated.
- If on combined modality therapy -notify responsible Radiation Oncologist and hold radiation therapy, be aware if pelvic irradiation is underway that myelosuppresion may be worse than what would be expected by fluorouracil alone. - Avoid medications that might interfere with absorption of the antidote (e.g., bismuth subsalicylate, sucralfate, cholestyramine) and use caution with medications that are metabolized by cytochrome P450 2C9 (e.g., phenytoin, clozapine). 12 - Consider contacting PADIS for additional information.
- Consider an ACEI to reduce risk of 5FU-related cardiac dysfunction.
- Inform administration, medical, nursing and pharmacy leadership of the patient event. Please note Alberta Health Services (AHS) insite links may only be accessed on AHS computers Guideline Resource Unit Appendix A: Estimated Weights of Baxter Elastomeric Infusors
The Baxter Elastomeric Infusors weights included below are an estimate determined by an Alberta CancerControl pharmacy quality control project. 11 The fluorouracil concentration varies between each patient's pump, but the total volume and flow rates are constant at 230 mL and 5 mL/hr. The weight of the pump empty is approximately 83.4 g. This is inclusive of the pump, its protective bag, label etc. to reflect the reality in a clinic setting that someone would have to weigh the pump. The weight of the pump full, with 230 mL of fluorouracil solution is approximately 316 g.
The following sample calculations can be used to estimate fluid administered and remaining (with the assumption that the specific gravity of the fluorouracil solution is 1.0 g/mL):

# Figure 1. Weighing of a Baxter Elastomeric Infusor
Step 3 -When the information in Step 1 has been received by Wellstat, the following documents will be sent to the hospital in which the patient will receive treatment with uridine triacetate. The physician treating the patient and a legally responsible party at the hospital will be required to complete these documents. As soon as the documents are returned to Wellstat, arrangements will be made to ship the uridine triacetate to the hospital where the patient is to receive treatment.
- Indemnification Agreement - Non-Disclosure Agreement - Physician's Agreement - Synopsis: Clinical Operations Procedure - Written authorization from your regulatory authorities allowing shipment of uridine triacetate into your country to the patient/hospital where the patient will be treated - A Guarantee of Reimbursement There is another set of documents that will be sent to the treating physician once the first set of documents has been returned to Wellstat. This second set of documents does not need to be returned immediately to Wellstat.
Appendix B Instructions for Obtaining Uridine Triacetate 13 Note that Uridine Triacetate (Vistogard) is approved for use in the United States only. Wellstat does provide uridine triacetate on a compassionate use basis, however, it can only be shipped to the hospital in which the patient is being/will be treated.
Step 1 -Physician to contact Wellstat at one of the following phone numbers: Emergency hotline 443-831-5626; Wellstat Safety Phone 240-479-1078 or 240-479-1073 or 800-914-0071
Wellstat requires that the following information on the patient potentially needing treatment with uridine triacetate be provided prior to the shipment of the uridine triacetate. - If the overdose was with infusional 5-FU, was a 5-FU bolus dose given? If so, how much and how long prior to the infusion was the bolus dose administered? - If this is a case of early onset of toxicities after treatment with 5-FU infusion or capecitabine, has the patient been tested for DPD deficiency? If so, are the results available? - If this patient is experiencing early onset of serious toxicities, please provide a list of the symptoms the patient has been experiencing and is currently experiencing.

# - Does the patient have compromised renal function?
Step 2 -Physician (with assistance from clinical pharmacist) to obtain Health Canada (HC) approval to treat by completing and submitting Special Access Program Form A.  Fax completed Form to (613) 941-3194, and then phone (613) 941-2108 to speak to an HC SAP agent to request an emergency verbal approval. (If after hours, leave message as per instructions, leave all details of your request with phone number for them to call back).

# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial GI Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, urologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial GI Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2016 and updated in 2022.
A formal review of the guideline will be conducted in 2025. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.

# Copyright  (2022) Alberta Health Services
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# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.