Regulatory Decision Summary for Acetaminophen Injection

The purpose of this New Drug Submission (NDS) was to obtain market authorization for intravenous (IV) Acetaminophen Injection for the treatment of pain and fever in adults and children. Upon review, the pediatric indication for children less than 2 years of age was not authorized. The submission relied on the prior findings of safety and efficacy of Ofirmev (acetaminophen IV), approved in the United States in 2010 and Canada in 2013, as well as over 10 years of market safety for Perfalgan (acetaminophen IV) in Europe and 10 years of market safety for the sponsor’s own product, initially approved as a generic version of Perfalgan in Europe in 2012.

The Sponsor’s Acetaminophen Injection demonstrated physicochemical comparability to two international reference products, Perfalgan and Ofirmev, both considered to be identical products. Based on these similarities, the efficacy and safety for Acetaminophen Injection was established using the third-party clinical trial results from Ofirmev, which have been previously reviewed by Health Canada. These results included data from three Phase III placebo-controlled trials; two for the management of pain and one for the treatment of fever to support efficacy in adults; and two active-controlled and three open-label safety and pharmacokinetic trials to support efficacy in the pediatric population (2 years of age and older). In pediatric patients younger than 2 years of age, the safety and efficacy for the treatment of acute pain and fever have not been established. Thus, Acetaminophen Injection was not recommended for this age group.

The safety data from these clinical trials demonstrated that intravenous (IV) injectable acetaminophen was safe and well tolerated as used under the conditions of the studies. Extensive global post-market experience, including more than 10 years as an injectable intravenous formulation further supported the well-characterized safety of injectable acetaminophen. Hepatotoxicity is the primary safety concern associated with acetaminophen use, and this is a well-known risk that is more common in instances of overdose or in at-risk individuals. Hepatotoxicity data provided in this review raised questions regarding the recommended duration of use, which remains an uncertainty. As hepatotoxicity events have been observed after relatively short periods of use, the proposed indication was revised to recommend the short-term use only. In addition, there is a risk of medication error related to potential confusion between milligram (mg) and millilitre (mL) during drug prescribing and administration, particularly in patients requiring weight-based dosing (i.e., patients weighing less than 50 kilograms [kg]). An error of this type could potentially lead to a 10-fold overdose situation. These risks were highlighted in the Product Monograph for the prescribers’ attention.

A comprehensive Risk Management Plan was developed between Health Canada and the sponsor, including monitoring for instances of overdose and label confusion, off-label use in children under 2, and hepatotoxicity events.

Based on the totality of the evidence, which included the well-established safety profile of acetaminophen, the anticipated short-term use, and the close safety monitoring in a hospital setting, the benefit-harm-uncertainty balance for Acetaminophen Injection was considered to be positive. The major risks of hepatotoxicity and medication dosing errors were mitigated through labelling in the agreed upon Product Monograph (dated January 25, 2023) and adequate post-market pharmacovigilance activities and risk mitigation measures have been put in place.

For further details about Acetaminophen Injection, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.