Hyperkalemia with fatal outcome during (liposomal) amphotericin B treatment

In rare cases, intravenous administration of (liposomal) amphotericin B treatment can cause severe, difficult to treat hyperkalemia that arises during or within several hours after start of infusion. Pharmacovigilance centre Lareb received 13 safety reports on this serious adverse reaction of which 6 had a fatal outcome.

Intravenous (liposomal) amphotericin B is used in the treatment of severe fungal infections. Currently, only the liposomal formulation is prescribed since it has a lower chance of severe nephrotoxicity compared to the conventional formulation. In the summary of product characteristics of both conventional amphotericin B (Fungizone) and liposomal amphotericin B (AmBisome), hyperkalemia is labelled as an adverse drug reaction. For Fungizone, the risk of hyperkalemia is described in association with rapid intravenous infusion especially in patients with decreased kidney function. For AmBisome, however, only the risk of hypokalemia is described in the special warnings and precautions for use section for which suppletion of potassium can be warranted.

Reports at Lareb
Kidney function was normal in most safety reports or patients underwent renal replacement therapy. Amphotericin B was administered by slow intravenous infusion in most cases. Hyperkalemia arises during or within several hours after start of intravenous amphotericin B infusion, is severe and refractory to treatment with consecutive fatal cardiac arrhythmias in some cases. The acute hyperkalemia can occur with the first intravenous administration or within several days or weeks of treatment. Even in cases with a longer treatment duration, the acute hyperkalemia arises during or within several hours after start of intravenous infusion. Causality seems plausible considering the temporal relation in the absence of alternative causes. The underlying mechanism remains unclear but is independent of nephrotoxicity or rapid infusion. In a few safety reports, however, potassium levels increased more gradually and less severe later on during treatment with concurrent decrease of kidney function and a mild course.

Further action
Pharmacovigilance centres in Europe received a total of 76 safety reports on hyperkalemia during intravenous (liposomal) amphotericin B treatment of which 28 had a fatal outcome. Monitoring of potassium levels during and in the first hours after infusion could be helpful in preventing a fatal outcome by early detection. Additional vigilance is warranted in case of concurrent potassium suppletion. Pharmacovigilance centre Lareb has shared these findings with the Medicines Evaluation Board on which a European procedure is started. More will be announced later this year.

Update 12-2-2024: It has been decided that the summary of product characteristics of liposomal amphotericin B (AmBisome and Abelcet) needs to be adapted. Risk of severe hyperkalaemie will be added to paragraph 4.4 Special warnings and precautions for use. Monitoring of potassium levels before and during treatment is recommended.