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.