Discussion
Main findingsWe found an unexpected interaction between certain OXY and TXA products after mixing them in vitro and observing for up to 60 minutes. The interaction significantly impacted OXY content leading to reduction in concentration within a short period of time.
The results of the two experiments indicate that mixing some combinations of OXY and TXA injection in 0.9%w/v saline solution or Ringer’s Lactate results in an immediate and significant (14.8% - 29.0%) loss of OXY as measured against the target concentration. In a subset of the combinations where losses are observed, the concentration continues to decline after mixing and throughout the stability assessment period (up to 3 hours). These results were observed across both infusion fluids.
The initial exploratory investigation (Part 1) suggested some indications as to possible causes for this phenomenon. Specifically, the presence of impurities in the TXA product that, when combined with each of two OXY products, may have led to loss of OXY on mixing and throughout the stability period. Also, the possibility of surface adhesion of OXY within the infusion bag cannot be ruled out as contributing to the observations upon mixing. However, the subsequent screen of multiple OXY-TXA injection combinations in 0.9%w/v saline (Part 2) indicates that other factors may be contributing to the effects observed. Firstly, these experiments were conducted in deactivated amber glass HPLC vials, selected to minimise surface effects, yet a similar phenomenon was observed. Secondly, the combinations where OXY losses were observed did not correlate completely with TXA products where significant impurity content was observed on the HPLC chromatograms. We have previously reported quality issues with samples of TXA collected from the clinical sites involved in the E-MOTIVE Trial3 in terms of excessive impurity content. While seven of the 18 TXA products used in this study showed similar deficiencies, only four of five affected combinations in Part 2 of the study contained TXA products with significant impurity profiles. Finally, one quality assured TXA product (TXA 8) was evaluated with two OXY products (OXY 1 and OXY 2) and loss of OXY on mixing was observed only in combination with one OXY product (OXY 2). This may indicate that some characteristic of the oxytocin product contributes to these effects.
It is worth noting that the ratio of the OXY injection product (10IU, 17µg/mL) concentration to the TXA injection product (500mg/5mL) is very small. Consequently, reactive species present at a proportionally low level within the TXA product, while meeting all quality specifications for the TXA product, might be present at concentrations in the same order as the OXY and could feasibly lead to a substantial loss of OXY, if an interaction were to occur.
Strengths and LimitationsThe strength of this study is that it is the first to examine the compatibility of these two life-saving medications in the context of PPH treatment. In addition, the samples analysed were collected from the point of use in clinical sites in lower and middle-income countries and therefore, represent commodities that would be available for combination if sites were to adopt a co-administration approach in implementing the E-MOTIVE protocol. The main limitation of the study is the small numbers of samples analysed due to constraints on the availability of products for testing. In Part 1 of the study, samples were prepared in duplicate, while in Part 2, only single evaluations of the compatibility of each combination were conducted.