Uridine triacetate serves as antidote for capecitabine, 5-FU overexposure

Uridine triacetate safely and rapidly reversed severe acute cardiotoxicity and neurotoxicity from overdose of capecitabine and 5-FU chemotherapy, according to results of two open-label clinical studies.

Patients who have greater sensitivity to 5-FU or capecitabine may develop severe and life-threatening toxicities — which manifest as severe forms of common toxicities like mucositis and cytopenia, but can also include central neurotoxicity and acute cardiomyopathy — during or quickly after administration. Further, 5-FU overdoses can also occur due to infusion pump errors and dosage miscalculations, and capecitabine can be ingested during suicide attempts or accidentally.

Uridine triacetate (Vistogard, Wellstat Therapeutics) delivers high concentrations of uridine, which can compete with 5-FU metabolites, and has been approved to treat adults and children who present with severe toxicities or overdosed with 5-FU or capecitabine.

Wen Wee Ma, MD, of the department of oncology at Mayo Clinic in Rochester, Minnesota, and colleagues evaluated final overall safety and efficacy data from two compassionate use trials conducted in 173 adults and children (mean age, 58.1 years; 43.4% female) who overdosed with 5-FU or capecitabine (n = 147) or who presented with early onset of severe toxicity (n = 26).

Overdose cases included six children, including one child with an autoimmune disease who received 5-FU instead of cyclophosphamide, three children aged 1 to 3 years who accidentally ingested a family member’s capecitabine, and two children with cancer who received an overdose of 5-FU. There also were six suicide attempts with capecitabine among adults.

All overdose patients received 1.9 to 576 times the planned infusion rate of 5-FU or doses up to 10 times higher than intended.

Researchers compared these data with a historical cohort of 25 patients who receive supportive care for overdose, which included antiemetics, IV fluids, antibiotics, intensive care and medications for myelosuppression.

Survival 30 days after overdose or appearance of toxicity served as the study’s primary endpoint.

Of the 142 evaluable overdose patients, 137 (96%) survived 30 days — this included all the patients with suicidal overdoses and cases of accidental ingestion by children. The historical 30-day survival rate for overdose patients was 16% (n = 4).

Fifty-three of 141 (38%) evaluable overdose patients with cancer resumed chemotherapy within 30 days (mean time to resumption of chemotherapy, 19.6 days).

Eight of the 26 patients with early-onset toxicity initiated treatment with uridine triacetate within 96 hours. Only three of eight patients who initiated uridine triacetate beyond 96 hours survived. The other five patients died of 5-FU toxicities, including acute respiratory distress syndrome (n = 1), multisystem organ failure secondary to sepsis (n = 1) and septic shock (n = 3).

The most common adverse reactions to uridine triacetate included vomiting (8.1%), nausea (4.6%) and diarrhea (3.5%).

“The frequency of overdoses is unknown, but with at least 275,000 patients in the United States receiving multiple cycles of 5-FU annually — most adjusted for a patient’s body surface area — a substantial number of unreported overdoses probably occur,” Ma and colleagues wrote.

“If we assume that overall incidence for the risk for developing severe toxicity is greater than 10%, it is not unrealistic to conclude that the frequency of early-onset patients in reality is probably much higher than the frequency of patients with overdose. This reinforces the need for physicians, nurses and patients to remain vigilant for signs and symptoms of early-onset severe toxicity, especially during the initial course or courses of 5-FU and capecitabine, and to be prepared to treat it urgently.” – by Alexandra Todak

Disclosure: Ma reports no relevant financial disclosures. Other researchers report employment with BTG International, a partner of Wellstat Therapeutics, as well as with Wellstat Therapeutics.