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Metabolic acidosis and paracetamol-flucloxacillin

Date: 29 October 2015

The Netherlands Pharmacovigilance Centre Lareb received 10 reports (including 6 published case-reports) of an adverse drug interaction between paracetamol and flucloxacillin which resulted in a metabolic acidosis. All received cases concerned women with an average age of 73 years (52-87 years). The average reported time between the beginning of the latest started drug or increase of dose of one of the two drugs and the metabolic acidosis is 24 days (9-60 days), the mean reported time is 21 days. In one case the time is not reported.

The proposed mechanism of this interaction lies in the gamma-glutamyl cycle. Glutathione deficiency by paracetamol removes the feedback inhibition resulting in the formation of gamma-glutamyl cysteine and elevated concentrations of gamma-glutamyl cysteine lead to the formation of 5-oxoproline, an acid residue. Flucloxacillin inhibits 5-oxoprolinase which enhances the accumulation of 5-oxoproline.

Several publications mention female sex, malnutrition, and infectious disease as possible risk factors for high anion gap metabolic acidosis. Women are more likely to acquire 5-oxoproline acidosis, possibly due to gender differences in the enzyme activities of the gamma-glutamyl cycle. Other conditions that seem to predispose for this disorder are pregnancy, vegetarian diet, sepsis, chronic renal insufficiency, and/or hepatic dysfunction, especially liver disease that results from chronic alcohol use. Although the literature is indicative, the proportion of older females in the received cases is striking. Unfortunately, except for the contracted infection for which flucloxacillin is administrated, there are no data of other risk factors. 

The reported cases to the Netherlands Pharmacovigilance Centre Lareb show a possible adverse drug interaction between paracetamol and flucloxacillin. We recommend extra alertness for patients treated with both drugs during a period longer than two weeks, especially when they are female, older and have risk factors.

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