Possible interaction between gliclazide, fluconazole and sulfamethoxazole resulting in severe hypoglycaemia

Hypoglycaemia in acquired immunodeficiency syndrome (AIDS) was mostly encountered when pentamidine was used to treat Pneumocystis carinii pneumonia [1]. We report the case of an HIV-infected patient with diabetes mellitus who developed hypoglycaemia when treated with gliclazide, sulfamethoxazole and fluconazole. To our knowledge, hypoglycaemia had never been linked to the interaction between these drugs.

Case report

A 56-year-old HIV-infected patient was admitted to hospital because of weakness and aggressive behaviour. He was known to have diabetes mellitus and had been treated with gliclazide (160 mg day⁻¹) for 2 years without previous evidence of hypoglycaemia. AIDS had been diagnosed 2 months earlier because of oral candidosis treated with fluconazole (50 mg day⁻¹) for 2 weeks. CD4 lymphocyte count was 42/mm³ and plasma HIV viral load was 12700 RNA copies ml⁻¹. Prophylactic treatment with sulfamethoxazole (400 mg day⁻¹) and trimethoprim (80 mg day⁻¹) was started. Antiretroviral treatment was refused. Two months later, 1 week after reintroduction of fluconazole at a higher dose (200 mg day⁻¹), he presented with weakness and disturbed behaviour. On examination, he was afebrile and there was no sensorimotor deficiency but there was hyporeflexia in his legs. A computed tomographic scan of the head was normal. Haemoglobin level and CD4 lymphocyte count were 10 g dl⁻¹ and 50/mm³ respectively. All other laboratory tests were normal, except for a blood glucose concentration of 2.2 mmol l⁻¹. Gliclazide was stopped. Two days later, the patient had a brief loss of consciousness while he was driving his car. His condition then improved. Neurologic symptoms did not recur during 3 month follow-up without retreatment with gliclazide.

Hypoglycaemia occurring in diabetic patients treated with sulphonylurea drugs has been well documented. In a multicentre study of hypoglycaemia induced by sulphonylureas between 1985 and 1990, gliclazide was implicated in 55% (46/98) of cases and the main cause was drug interactions, suspected in nearly 50% of cases [2]. The most frequent drug interaction involved miconazole (9/49) that inhibits, like fluconazole, cytochrome P4502C9 (CYP2C9) [3].

Data from studies with rat livers suggest that gliclazide is mainly metabolized by the same cytochrome (CYP2C9) as tolbutamide and to a lesser extent by CYP2D6 [4, 5]. Our patient received a high dose of fluconazole and gliclazide. Fluconazole might have strongly inhibited CYP2C9 and increased the serum concentration of gliclazide. Sulfamethoxazole also inhibits CYP2C9 and could have contributed to hypoglycaemia [2, 3].

The relapse of neurologic symptoms 2 days after discontinuation of gliclazide was compatible with an increase in its half-life (normal half-life = 10–14 h) as it was reported that tolbutamide half-life was enhanced three fold in patient receiving CYP2C9 inhibitor [6].

We believe fluconazole coadministered with sulfamethoxazole resulted in inhibition of gliclazide metabolism leading to severe hypoglycaemia. Physicians should consider this potential interaction in the management of HIV-infected patients in whom highly active antiretroviral therapy frequently triggers diabetes mellitus.