Increased Incidence of Symptomatic Hyponatremia with Voriconazole Prophylaxis during Cyclophosphamide Based Conditioning in Patients Undergoing Hematopoietic Stem Cell Transplantation

Background: Voriconazole (vori) is routinely used for prophylaxis against fungal infections in BMT. However, vori has interactions with drugs used in transplant which affect the pharmacokinetics or pharmacodynamics of each other. These interactions are due to the ability of many drugs to inhibit or induce isoenzymes of cytochrome P-450 family. We had initially reported on therapeutic drug monitoring (TDM) of vori that systemic steroids and cyclosporine decrease vori levels which could have clinical implications of break through fungal infections. Cyclophosphamide (Cy) in high dose chemotherapy regimens is known to cause hyponatremia possibly due to SIADH. In the present study, we report increased incidence of symptomatic hyponatremia (SHN) in a cohort of patients where vori was used concomitantly with Cy based conditioning. To our knowledge this is first such report.

Methods: All patients (autologous-129 allogeneic- 95) who received vori prophylaxis during peritransplant period between September 2008 and January 2014 were included. Vori prophylaxis was started at least 3 days prior to start of conditioning regimen in all patients before April 2011. Since April 2011, patients undergoing transplant received vori 1 day after completion of conditioning regimen unless started earlier due to recent history of systemic fungal infection. All patients above 12 years of age received oral or iv vori at a loading dose of 6 mg/kg (maximum 400 mg) 12 hourly on first day followed by 4mg/kg as maintenance. Patients less than 12 years received 7mg/kg 12 hourly. Trough vori levels were measured between day 5 and day 7 after start of the drug. Subsequent levels were done 2-4 weekly till discontinuation of drug. Conditioning regimens used for allogeneic transplant were either myeloablative (TBI-Cy or busulfan-Cy) or reduced intensity (fludarabine with either melphalan, busulfan or cyclophosphamide +/- 2 Gy TBI).Conditioning regimens for autologous transplants included LACE (lomustine- 200mg/m² d-7, ara-c- 2000 mg/m² d-6 and d-5,cyclophosphamide- 1800 mg/m² d-4 to d-2, etoposide- 1,000 mg/m² d-7) or BEAM for lymphomas, melphalan 200 mg/m² for multiple myeloma and BuMel for neuroblastoma and Ewing's sarcoma. Vori was continued for at least 100 days for all patients undergoing allogeneic transplant and longer if patients were on steroids due to GVHD. Autologous transplant patients received it for 28 days.SHN was defined as acute fall in serum level of sodium of greater than 10mEq/L or fall to less than 120mEq/l with any of the following symptoms i.e. headache, vomiting, confusion or seizures. Fluid restriction was advised for all patients and 3% hypertonic saline was used with rate of infusion adjusted so as to not increase the serum Na⁺ level more than 10mEq/L over 24 hours. Further doses of Cy were withheld if symptoms persisted or if Na⁺ level failed to normalize (i.e. >130 mEq/L) within 24-48 hours. Vori levels in plasma were determined by a validated HPLC assay.

Results: Two hundred and twenty four patients were monitored 953 times for vori levels during this period. The median number of TDM was 3 (1-32) per patient. One hundred thirteen patients received vori prophylaxis from the start of conditioning regimen while 111 received vori after completion of conditioning regimen. See Fig. 1.

SHN was seen only in patients who received Cy based conditioning therapy, 13 (23%) in the concomitant cohort compared to only 2 (3%) in the sequential group(P=0.0016). The median fall of Na ⁺ level was 14 mEq/L (5.2- 25.9).Six patients received hypertonic saline. One patient developed seizure. All patients recovered from hyponatremia. In the concomitant cohort, the median vori levels in patients who developed SHN was 2.8 ug/ml compared to 2.3 ug/ml in patients who did not (P= NS). Further doses of Cy were withheld only in 2 patients while deferred by 24-48 hours in 4 patients. All modifications in further Cy doses occurred in the concomitant group. No other drug was stopped including vori.

Conclusions: Concomitant use of vori with Cy based conditioning regimens increases the incidence of symptomatic hyponatremia. This suggests that vori affects the metabolism of cyclophosphamide possibly through cytochrome P-450 system that increases the risk of symptomatic hyponatremia. This interaction should be borne in mind in the setting of transplant and vori should be started after the completion of conditioning therapy wherever possible.

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