First Emergency Antidote to 5-FU Chemo in the US

Zosia Chustecka

Disclosures

December 11, 2015

For the first time, an antidote to certain types of chemotherapy has been approved by the US Food and Drug Administration (FDA).

The product is uridine triacetate (Vistogard, Wellstat Therapeutics Corporation), and it is approved for the emergency treatment of adults and children who have received an unintended overdose of 5-fluorouracil (5-FU) or capecitabine (Xeloda), an oral prodrug that is converted to 5-FU in the body. The product is also intended for emergency use in patients who develop certain severe or life-threatening toxicities within 4 days of receiving these chemotherapies.

"Today's approval is a first-of-its-kind therapy that can potentially save lives following overdose or life-threatening toxicity from these chemotherapy agents," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research.

Commonly Used Drugs, Fewer Common Problems

Fluorouracil (administered by infusion) and capecitabine (taken orally) are both widely used in the treatment of cancer, especially breast and colorectal cancers.

An overdose of fluorouracil or capecitabine is rare, but when it occurs, the effects are serious and can be fatal, the FDA explains.

In addition, some patients develop serious toxicity with these agents, even when they are administered at standard doses. These drugs carry a risk for early severe toxicity (seen in about 25% of patients after the first cycle) and even death as a result of severe toxicity (in about 0.4% to 0.6% of patients, which amounts to some 1300 patients per year in the United States), according to Jean-Philippe Metges, MD, from CHU Hôpital Morvan in Brest, France, as previously reported by Medscape Medical News. The toxic reaction is related to an asymptomatic deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, Dr Metges explained. People who have a complete DPD deficiency — which is rare — suffer multiorgan toxicity, which can be fatal; in these people, fluoropyrimidine drugs should be avoided. In people with the more common partial DPD deficiency, the drugs can be used, but at reduced doses to reduce the risk for toxic effects, he said. As previously reported, there has been research showing that prescreening patients for this deficiency, and then using lower doses, can reduce the risk for these toxicities.

Antidote Is Taken Orally

In the FDA notice about the new approval, the agency explains that uridine triacetate, which is taken orally, works by blocking the cell damage and cell death caused by fluorouracil chemotherapy.

Patients should take the product as soon as possible after the overdose (whether or not they have symptoms) or early-onset (within 4 days) of severe or life-threatening toxicity.

The product is not indicated for nonemergency use because it may lessen the efficacy of fluorouracil, the agency cautions.

The approval is based on data from two clinical trials involving 135 adult and pediatric cancer patients who either received an overdose of fluorouracil or capecitabine, or had early-onset, unusually severe, or life-threatening toxicities within 96 hours after receiving fluorouracil (not due to an overdose). The primary measure of efficacy in these trials was survival at 30 days or until chemotherapy could resume if prior to 30 days.

Of those who were treated with the antidote for overdose, 97% were still alive at 30 days. Of those treated with the antidote for early-onset severe or life-threatening toxicity, 89% were alive at 30 days.

In both studies, 33% of patients resumed chemotherapy in fewer than 30 days.

The most common adverse effects of treatment with uridine triacetate reported in these clinical trials were diarrhea, vomiting, and nausea.

Principal investigator of the Vistogard clinical development program, Wen Wee Ma, MD, associate professor of the oncology, GI cancers, and drug development program at the Roswell Park Cancer Institute in Buffalo, New York, commented in a statement: "Severe 5-FU toxicity has, historically, been difficult to treat and sometimes resulted in death for those affected. It is important to recognize the signs of severe 5-FU and capecitabine toxicity early, which often include unexpected side effects on the first cycle – including gastrointestinal toxicities such as mucositis, central nervous system toxicities such as altered mental state, hematologic toxicities, and even cardiotoxicity. The approval of Vistogard is important because it represents the first treatment with a demonstrated track record of efficacy and, just as important, it allows some patients to resume chemotherapy sooner following the resolution of the toxicity."

The FDA has granted Vistogard orphan drug designation, priority review, and fast track designations, which expedites the review process for drugs that have potential to benefit patients with serious or life-threatening conditions.

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