Enteral voriconazole induced hypoglycemia: A potentially life threatening complication.

Voriconazole is a newer effective antifungal agent currently available for the treatment of invasive aspergillosis. The case we present describes an episode of serious persistent hypoglycemia after voriconazole therapy and we believe that this strongly contributed to this event. It is a warning to all that voriconazole has a propensity to alter glucose homeostasis in the presence of kidney disturbance.

Introduction

Voriconazole is the most effective replacement for amphotericin B currently available for the treatment of invasive aspergillosis.[12] Incidences of serious adverse events in patients receiving voriconazole are under reported.[3] We report a case of severe hypoglycemia after normal enteral voriconazole dose in a nondiabetic patient with acute kidney injury and near normal liver function. The temporal relationship of voriconazole administration and the hypoglycemic episode suggests that voriconazole strongly contributes to the precipitating event.

Case Report

A 45-year-old farmer was admitted to our ICU in an unconscious state following snake bite five days before. He was otherwise healthy with no co-morbidities. His hemogram, serum glucose and liver function test were within normal limits. Patient had altered renal profile (creatinine 8 mg/dl) due to rhabdomyolysis requiring hemodialysis. After few days of mechanical ventilation, he developed ventilator-associated pneumonia. His tracheal aspirate cultures were negative for bacterial and atypical pathogens but had heavy growth of Aspergillus fumigatus. Intravenous voriconazole therapy was not advised on account of renal failure. His liver function test (LFT) and serum glucose were normal on that day. As he was tolerating enteral feeds well, he was given enteral voriconazole(Vfend; Pfizer; New York) 400 mg 12-hourly (loading doses) followed by 200 mg 12-hourly daily (maintenance) through nasogastric tube. Twenty hours after initiation of voriconazole (just before 3rd dose), the patient developed drowsiness, and his plasma glucose level was detected to be 41 mg/dl. He was immediately treatedwith multiple boluses of 25% dextrose but since hypoglycemia persisted we had to start 50% dextrose by continuous infusion @ 50-100 ml/h for the next 48 h to maintain euglycemia. There was no history of accidental insulin injection. All prescribed drugs interactions (meropenem, ranitidine, paracetamol, low molecular weight heparin) were checked strictly in view of dispensing errors of any hypoglycemic agents. Insulin plasma concentrations of 25.8 μU/ml (normal range 2.6-24.4 μU/ml) were higher than normal and C-peptide concentrations 3.8 ng/ml (normal range 0.9-4.0 ng/ml) were also observed to be in the high normal range. Thyroid hormone and cortisol assays were within normal limits. MRI of the pancreas was normal. Endocrinology consultation was taken. Hypoglycemia was probably due to voriconazole therapy and therefore we changed it to amphotericin B on 3rd day. However, we could not do the plasma voriconazole assay (high performance liquid chromatography and/or liquid chromatography–tandem mass spectrometry)[1] as they are costly and not available in our country. Within 18 h of stopping voriconazole and starting amphotericin B, 50% dextrose infusion could be stopped. Repeat insulin and C-peptide plasma concentrations were later noted (16.8 μU/ml and 2.2 ng/ml respectively) to be within normal range. Repeat episode of hypoglycemia did not occur during his stay in hospital.

Discussion

Hypoglycemia is a potentially fatal, yet preventable problem in intensive care setting. Common causes of hypoglycemia in non-diabetics include drugs, chronic renal failure, alcohol intoxication, liver failure, sepsis, cancer and endocrine disorders.[4] Drug-induced hypoglycemia can be severe and may cause significant morbidity.[5]

Voriconazole is a triazole antifungal agent.[67] The primary mode of action of voriconazole is the inhibition of fungal ergosterol biosynthesis. Voriconazole has oral bioavailability of 96%.[8] Voriconazole is metabolized by the hepatic cytochrome P450 enzymes: CYP2C19 (highest), CYP2C9, and CYP3A4.[7] CYP 2C19 polymorphism leads to wide fluctuation in plasma levels of voriconazole, found in 15–20% of Asians.[7] A previous study has shown that the major metabolite, voriconazole N-oxide, inhibits the metabolic activity of these enzymes and increases voriconazole level.[6]

Toxicity reported with voriconazole includes changes in vision, hepatotoxicity, cognitive dysfunction and rash.[9] Though hypoglycemia with intravenous voriconazole is quoted in literature,[1] it is not reported till date with oral voriconazole. Moreover, the patient is neither diabetic nor taking any oral hypoglycemic agent. Whipple's triad[10] (symptoms consistent with hypoglycemia, a low plasma glucose concentration and resolution of hypoglycaemic symptoms by glucose administration) present in our case is suggestive of either an increased secretion or decreased breakdown of endogenous insulin. This is probably the principal underlying mechanism of hypoglycemia in our case with evidence of a high normal range of insulin and C-peptide levels. Especially in a critically sick patient as ours, we expect hyperglycemia due to stress. Hypoglycemia for a prolonged period with a higher than normal insulin and high normal c peptide level made it clear that prolonged hypoglycemia was all due to excess insulin in that patient at the time of investigation. Further literature search reveals that renal failure may reduce insulin requirements dramatically and increase the potential for hypoglycemia in insulin- treated and insulin-secreting patients, at least partially, due to reduced clearance.[11] Though the exact interaction between insulin and voriconazole is not clear, hypoglycemia in our case is likely to be due to decreased degradation of insulin with renal dysfunction.

According to WHO-UMC casualty assessment criteria, a probable/likely adverse drug reaction is a clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals and which follows a clinically reasonable response to withdrawal.[12] In our case also, there was a close relation between voriconazole initiation and hypoglycemia onset with laboratory test abnormality, unlikely in an underlying sepsis condition and a hypoglycemic reversal to withdrawal of drug was present. Rechallenge information is not required. According to Naranjo probability scale method of adverse drug reaction, serious persistent hypoglycemia after voriconazole therapy is probable (Naranjo total score 8).[12] However, further studies are required to address the above issue, but as of now we suggest that plasma concentration of voriconazole along with blood insulin levels should be done in larger number of patients to probe the above probability.

Clinicians need to be aware about the risk of hypoglycemia after enteral voriconazole in the background of acute kidney injury even in non-diabetic patients, and may advise their patients to monitor plasma glucose levels routinely in background of acute kidney injury.