Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy

Background: We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. Methods: To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. Results: All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 μmol/L ± 6.41 vs 2.54 ± 0.67 lmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. Conclusions: Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in posttransplant patients with long-term voriconazole use.