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Journal of Postgraduate Medicine, Vol. 56, No. 1, January-March, 2010, pp. 44-45 ADR Report Interaction between voriconazole and glimepiride Shobha JC, Muppidi MR Department of Clinical Pharmacology, Nizam's Institute of Medical Sciences, Hyderabad-500 082, India Correspondence Address: Dr. J C Shobha, Department of Clinical Pharmacology, Nizam's Institute of Medical Sciences, Hyderabad-500 082, India, jcshobha@yahoo.com Date of Submission: 13-Apr-2009 Code Number: jp10017 PMID: 20393255 DOI: 10.4103/0022-3859.62422 Abstract Voriconazole, a triazole antifungal, is gaining popularity in the treatment of invasive fungal infections, mostly in the immuno-compromised patients. Voriconazole, a CYP2C9 inhibitor, has many potential drug interactions. Its interactions are both due to its pharmacokinetic properties and the genetic polymorphism of CYP2C9 enzymes. Here is a case report of one such drug-drug interaction between voriconazole and glimepiride, an oral hypoglycemic agent, which led to prolonged and persistent hypoglycemia for 48 h. It was diagnosed by the temporal association of the occurrence of symptoms with voriconazole intake. The patient stabilized on withdrawal of the responsible drugs. Due to the high incidence of co-prescribing voriconazole with other drugs, caution has to be exercised while prescribing it. Clinicians' awareness, a high index of suspicion and constant monitoring for adverse drug reactions, expected or unexpected drug interactions has to be emphasized, even if the co-prescribed drugs are in normal therapeutic doses.Keywords: Drug interaction, glimepiride, hypoglycemia, voriconazole Voriconazole is a triazole antifungal medication which is gaining popularity over Amphotericin B, for serious, life-threatening, invasive fungal infections which are generally seen in immunocompromised patients. They include candidiasis, aspergillosis and certain emerging fungal infections. [1] It is also indicated for prophylaxis as well as for empirical antifungal therapy in immunocompromised patients with febrile neutropenia who are at a high risk for breakthrough fungal infections. [1] Voriconazole, a CYP2C9 inhibitor has to be cautiously prescribed as it has many potential drug interactions. [2] Especially with CYP2C9 substrates, we need to exercise more caution as the genetic polymorphism of CYP2C9 adds to the unexpected possibility of adverse drug reactions and drug-drug interactions even at normal therapeutic doses. [3] Here is a case of such a potential interaction between voriconazole and glimepiride at therapeutic doses, which has not been studied clinically. [2] Case Report A 69-year-old male with Myelodysplasia RAEB II (on 5-Azacytidine chemotherapy) progressed to acute myeloid leukemia and developed febrile neutropenia. He was a known diabetic for seven months on Tablet glimepiride (Amaryl) 1 mg OD with good glycemic control. As empirical antifungal therapy was indicated, Tablet voriconazole (Vfend) 400 mg 12-hourly (two doses) followed by 200 mg 12-hourly daily orally was started. Baseline liver function tests, renal function tests and ophthalmic examination were done before starting the course. The patient was instructed to take the tablet one hour before or after food and was asked to report immediately if visual disturbance, rash or gastrointestinal disturbances occurred. On the second day of the course, two hours after the first 200 mg dose of voriconazole, the patient suddenly developed excessive and pressured speech, confusion and delirium. His blood glucose was recorded to be 40 mg/dl. Serum electrolytes and liver function tests were found to be normal. Immediate 25% dextrose infusion stabilized the patient. Despite constant monitoring, the patient dropped into unconsciousness two hours after stabilization. It was found that he had hypoglycemia (blood glucose=38mg/dl). With 25% dextrose, the patient regained consciousness. Suspecting a drug-drug interaction, voriconazole and glimepiride were stopped. An hourly blood glucose monitoring for a day followed by two-hourly monitoring revealed that the patient had persistent and prolonged, hypoglycemia which lasted for a period of 48 h after withdrawing the drug. He was unable to maintain normal blood glucose levels if the dextrose infusion was stopped. The patient was treated with continuous infusion of 5% dextrose and non-diabetic diet until he stabilized on the third day with maintainable blood glucose levels. Tab. voriconazole was restarted and glimepiride was substituted with subcutaneous insulin for the rest of the period. No such reaction or hypoglycemia occurred further in the course of treatment. Discussion Voriconazole and its metabolites are inhibitors of CYP2C9 liver enzymes. Glimepiride, a sulphonylurea is a substrate for CYP2C9 enzymes. Voriconazole inhibited the metabolism of glimepiride and prolonged its action which led to the persistent hypoglycemia. Also, CYP2C9 iso enzymes exhibit genetic polymorphism which is why its substrates can cause unexpected adverse effects or drug-drug interactions even under normal therapeutic doses. [3] The temporal association of persistent hypoglycemia and the administration of voriconazole is prominent and, the drug dechallenge led to maintainable blood glucose level. Glimepiride has a half life of 3.4 h, peaks at 2-3 h and has a duration of action of 12-24 h.The incidence of hypoglycemia with glimepiride is low (2%) when compared to other long-acting second generation sulphonylureas (20-30%). [4] In this patient, though the chance of glimepiride alone causing persistent hypoglycemia cannot be ruled out, the chances are low, more so, after seven months of good glycemic control. Even though voriconazole and glimepiride were administered in normal therapeutic doses, due to the chance of a potential pharmacokinetic drug interaction and the genetic polymorphism of CYP2C9, the patient had unexpected life-threatening hypoglycemia. Hence, clinicians′ awareness and close monitoring for adverse drug reactions and interactions has to be emphasized while prescribing drugs like voriconazole. It is advisable to monitor drug interactions known to occur with other azoles until more clinical reports and experience is gained with voriconazole. [5] References
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