Management of fluoropyrimidine overdose or overexposure

Fluorouracil (5-FU) and capecitabine are fluoropyrimidines widely used for the treatment of solid tumours. Exceeding the absolute dose or infusion rate can result in serious or life-threatening toxicity.

Fluoropyrimidine overdose or overexposure can manifest as severe forms of common adverse reactions such as mucositis, diarrhoea or cytopenias, or patients may quickly develop central neurotoxicities (e.g. altered mental state, encephalopathy and coma) and acute cardiac toxicities (e.g. arrhythmias, heart failure, and cardiac arrest) which can be fatal.^rr

Fluoropyrimidine overdose or overexposure may be due to:

• infusion pump malfunction or mis-programming
• dose calculation errors
• excess or accidental ingestion of oral fluorouracil analogues (e.g. capecitabine)
• concomitant drugs that inhibit fluorouracil metabolism
• dihydropyrimidine dehydrogenase (DPD) deficiency resulting in fluorouracil overexposure.

Clinicians should consider the possibility of metabolic deficiency when toxicities occur within the first 7 days. In such cases, it is advisable to consider immediate discontinuation of fluorouracil/capecitabine pending further evaluation.

Studies have shown that uridine triacetate (formerly known as vistonuridine) may be an effective antidote for fluoropyrimidine overdose or overexposure.^rr Uridine acetate is a pyrimidine analogue and acetylated pro-drug of uridine. Following oral administration, uridine triacetate undergoes deacetylation to yield uridine. Uridine competitively inhibits cell damage and cell death.^r

An oral formulation of uridine triacetate was approved by the US Food and Drug Administration (FDA) in December 2015 under the trade name Vistogard^®.

Administration of uridine triacetate^rr

• Uridine triacetate should be commenced as soon as possible after fluoropyrimidine overdose or overexposure (within 96 hours* following the end of fluorouracil or capecitabine administration).
• It is available as an orange flavoured sprinkle powder. The adult dose is 10 grams (1 sachet) orally every 6 hours for 20 doses. It may be taken with or without food.
• Mixing uridine triacetate with soft foods such as pudding, apple puree or yoghurt may help to  counteract the bitterness of the drug. Once mixed, it should be taken within 30 minutes.
• Uridine triacetate may be administered via a nasogastric tube or gastrostomy tube when necessary (e.g. severe mucositis, or coma).
• A 5HT₃ antagonist administered 30 minutes prior to the dose of uridine triacetate may help to ensure that it is retained and not vomited.
• Drug binders (e.g. cholestyramine) may bind to uridine triacetate and should be temporarily discontinued.

Detailed dosing instructions are provided by the company when a patient is enrolled for treatment.

*Note: the efficacy and safety of uridine triacetate initiated more than 96 hours following the end of administration of fluoropyrimidine drugs has not been established.^r There are isolated case reports of patients with fluoropyrimidine toxicity responding to uridine triacetate administered 7 and 21 days after the last fluoropyrimidine dose.^rr

The safety of uridine triacetate was assessed in 173 patients in 2 compassionate use, single arm, open-label, multicentre trials. Adult and paediatric patients presenting with fluorouracil or capecitabine overdose and/or a rapid early onset of severe fluorouracil or capecitabine toxicity were enrolled into the study. Patients received emergency treatment with uridine triacetate at a dose of 10 grams (or 6.2 g/m² for paediatric patients, maximum 10 grams per dose) orally every 6 hours for a total of 20 doses, commencing as soon as possible after fluorouracil or capecitabine and the recognition of the need for antidotal treatment. The primary efficacy endpoint was patient survival or the resumption of chemotherapy during the 30 day monitoring period.^r

Prior to uridine triacetate, the standard treatment for a fluoropyrimidine overdose was supportive care, including antiemetics, intravenous fluids, antibiotics, intensive care, and medications to treat myelosuppression. Therefore, in these studies, the overall efficacy of treatment with uridine triacetate was compared with a historical cohort of cases in which patients with a documented fluoropyrimidine overdose received best supportive care.^r

Of the 173 patients included in the study, 147 were treated with uridine triacetate following an overdose of fluorouracil or capecitabine and 26 patients were treated after exhibiting early-onset, severe, or life-threatening toxicities. Six out of the 173 patients were paediatric cases.^r

© Cancer 2017

Efficacy

Of the 173 patients treated with uridine triacetate, 158 patients (94%) survived to day 30 and 56 out of 173 patients had resumed chemotherapy prior to day 30. 

Overdose patients

There were 147 patients with a fluoropyrimidine overdose included in the study. 5 patients were lost to follow up, leaving 142 evaluable patients, of which 137 (96%) survived to day 30. 

In contrast, mortality was 84% (21 of 25 patients) in a historical cohort of patients who did not receive uridine triacetate.^r

Early-onset patients

Treatment with uridine triacetate was commenced within the first 96 hours for 18 out of the 26 patients presenting with early-onset severe toxicity and all 18 patients survived and recovered. 

Of the 8 patients who initiated treatment beyond 96 hours, 3 patients survived and 5 patients died. The deaths were attributed to sequelae of fluorouracil toxicities.^r

Toxicity

In the study there was a high rate of treatment compliance, with a median number of 20 doses taken per subject (range 3-23).

Overall, uridine triacetate is well tolerated by most patients. Mild to moderate nausea, vomiting and diarrhoea have been reported. ^rr

[%id%]

[%title%]

Read abstract

[%abstract%]

Version 4

Date

Summary of changes

23/08/2024

Document status updated from under review to endorsed. Management section updated with new product disturber/contact details for Australia clinicians: consignment stock of uridine triacetate is held at Peter MacCallum Cancer Centre (Victoria, Australia). References updated with BTG International Inc. Vistogard (uridine triacetate) product information, October 2023. Version number increased to V.4. Next review in 2 years.

Version 3

Date	Summary of changes
01/05/2018	Reviewed at the Medical Oncology Reference committee meeting on 16/02/2018. Background, management and evidence sections updated. References added.  Version number increased to V.3. Next review due in 2 years.
29/11/2018	Emergency number for Wellstat Therapeutics updated.
04/12/2019	Product distributor and contact details changed to WEP Clinical.
18/09/2020	Reviewed electronically by Medical Oncology Reference Committee. Management section updated. Next review in 2 years.
08/12/2022	Reviewed electronically by Medical Oncology Reference Committee. No changes. Next review in 2 years.
13/10/2023	Reviewed by Medical Oncology Reference Committee. Product distributor and contact details in the management section being reviewed as SERB Pharmaceuticals acquired the product from Wellstat on 1st September 2023 and has taken over the distribution of uridine triacetate from WEP. Document status updated to under review pending update from SERB Pharmaceuticals.
05/02/2024	Phone number for emergency ordering of Vistogard removed and replaced with email address as per correspondence from WEP Clinical. Still awaiting updated correspondence from SERB Pharmaceuticals. Document status remains under review.
08/03/2024	Vistogard is no longer distributed by WEP Clinical and emergency product order email address vistogard@wepclinical.com is no longer valid, as confirmed via correspondence on 8/03/2023. SERB Pharmaceuticals have acquired Vistogard and current SERB Pharmaceuticals contact details for emergency product orders are directly via phone  + 33 1 44 62 55 17 (preferred) and email address: astreinte@serb.eu, as confirmed via correspondence 8/3/2024. Management section updated to reflect SERB Pharmaceuticals contact details.  Document status remains under review.

Version 2

Date	Summary of changes
31/05/2017	Transferred to new eviQ website. Version number change to V.2.

Version 1

Date	Summary of changes
23/07/2010	New protocol taken to Medical Oncology Reference Committee meeting.
13/08/2010	Approved and published on eviQ.
29/02/2012	Reviewed, updated links.
30/06/2013	Reviewed, no changes and next review in 2 years.
17/10/2016	Emergency number for Wellstat Therapeutics updated.