Background

N-acetylcysteine (NAC) remains a mainstay antidote for acetaminophen-induced hepatotoxicity since an oral 72-hour regimen was approved by the U.S. Food and Drug Administration (FDA) in 1985. In 2004, the FDA approved an intravenous (IV) formulation administered in a three-bag protocol totaling 300 mg/kg over 21 hours: 150 mg/kg over 15 minutes, 50 mg/kg over 4 hours, and 100 mg/kg over 16 hours. The initial rapid infusion of 150 mg/kg over 15 minutes was frequently associated with rate-dependent, non–IgE-mediated anaphylactoid reactions, also called non-allergic anaphylactic reactions (NAARs). Subsequent post marketing surveillance and clinical data suggested that prolonging the duration of the initial infusion decreased the incidence of adverse effects. Accordingly, in 2011, the FDA recommended extending the duration of the first infusion from 15 minutes to one hour. Despite this modification, the complexity of preparing and administering three separate infusion bags continued to pose challenges for clinical staff, contributing to medication errors. Additionally, anaphylactoid reactions remained a concern.

Two-Bag Regimen Development

A 2016 prospective observational study (Isbister et al., 2016) compared the traditional 3-bag NAC to a simplified 2-bag regimen. The revised dosing combined the 1st and 2nd bag into a single infusion of 200 mg/kg over 4 hours, followed by a maintenance dose of 100mg/kg over 16 hours, maintaining the same total cumulative dose of 300 mg/kg over 20 hours. The study demonstrated a lower incidence of adverse reactions with the 2-bag dosing regimen. Subsequent studies supported these findings (McNulty et al., 2018; (Schmidt et al., 2018; Pettie et al., 2019). Wong et al. (2020) determined that the two-bag N-acetylcysteine regimen was non-inferior to the three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of acetaminophen overdose. These studies endorse the 2-bag regimen as a safe and effective alternative to the conventional 3-bag approach.