Fluri - Adverse Effects

Adverse Effects

Side effects include myelosuppression, mucositis, dermatitis and diarrhea.

5-FU injection and topical even in small doses cause both acute central nervous system (CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths.

When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population having dihydropyrimidine dehydrogenase (DPD) deficiency. There are laboratory tests to determine the relative activity of the DPD enzyme. It is expected that with a potential 500,000 people in North America using the pyrimidine-based 5-FU, this form of testing will increase.

The typical starting dose of capecitabine is 2,500 mg/m2 per day in Europe and 2,000 mg/m2 per day in the US. Probably the main action of 5-FU occurs when a 5-FU metabolite binds to thymidylate synthase. This binding is stable only in the presence of methylenetetrahydrofolate. It is speculated that this may explain why people in the US—a country that mandates adding folic acid to some foods—apparently require a lower dose of capecitabine than people in Europe, where countries do not mandate added folic acid.

The body converts both folic acid and leucovorin to methylenetetrahydrofolate. Each of those precursors amplified the effect of 5-FU in one animal study. However, another animal study seemed to indicate that, given the same 5-FU treatment, a special diet containing no folic acid worked better than the normal diet.

Folic acid may amplify the desired action and the toxicity of 5-FU. The exact mechanism of interaction is unknown.

When 5-FU is given intravenously, it is typically mixed with leucovorin in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40 mg/m2 to 140 mg/m2) had disappointing results and concluded that further studies were needed. There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.

One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda (capecitabine) had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers were unsure why.

Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs. Similarly, infusion of 5-FU and leucovorin via permanent indwelling catheters is complicated by catheter blockage due to calcium carbonate formation (Ardalan and Flores, 1995).

DPD deficiency, a pharmacogenetic syndrome leading to partial or total loss of ability to detoxify 5-FU in the liver, is strongly associated with increased risk of severe/lethal toxicities with 5-FU or oral 5-FU.

Some side effects of the topical version of Fluorouracil include redness, dryness, pain, erosion (loss of the upper layer of skin), swelling and burning.