Development and stability of a heat‐stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle‐income countries

Abstract

Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat‐stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30°C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60°C, for shorter periods of time. The development resulted in a heat‐stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25–5.65). The generated stability data of this formulation show that ≥95% purity of the peptide was maintained for a minimum of 3 years at 30°C, 6 months at 40°C, 3 months at 50°C and 1 month at 60°C. In addition, the heat‐stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle‐income countries, where maintaining cold chain distribution is difficult.Ferring Pharmaceuticals, the World Health Organization, and MSD# for Mothers have established a collaboration to develop this heat‐stable formulation of carbetocin for the prevention of post‐partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality.

Heat-Stable Carbetocin Versus Oxytocin to Prevent Hemorrhage After Vaginal Birth

“…The trial was motivated by the proven heat-stability profile of heat-stable carbetocin. 4 Although the United Nations Commission for Life-Saving Commodities recommends that oxytocin be supplied and stored between 2°C and 8°C to ensure efficacy, 13 in many settings oxytocin is still stored at room temperature, which leads to degradation and loss of efficacy in approximately one third of ampules. 3 In the present trial, we used highquality oxytocin and stored both the heat-stable carbetocin and the oxytocin between 2°C and 8°C to maintain blinding and to provide oxytocin the best chance of efficacy.…”

“…2, 3 Heat-stable carbetocin, an oxytocin analogue, does not require cold-chain transport and storage; it has been shown to maintain stability over a period of 36 months at 30°C and 75% relative humidity. 4 The heat-stable formulation of carbetocin differs from the existing non-heat-stable formulation only in its excipients.…”

International consensus statement on the use of uterotonic agents during caesarean section

“…There are concerns about a loss in potency of oxytocin during storage at high temperatures , which were not corroborated by other authors . The manufacturer states that carbetocin can be kept for 1 month at temperatures up to 60 °C, 3 months at 50 °C, 6 months at 40 °C and 3 years at 30 °C .…”

“…There are concerns about a loss in potency of oxytocin during storage at high temperatures [80], which were not corroborated by other authors [81]. The manufacturer states that carbetocin can be kept for 1 month at temperatures up to 60°C, 3 months at 50°C, 6 months at 40°C and 3 years at 30°C [82]. There is some evidence that an escalating strategy for the management of increased bleeding after vaginal delivery can reduce postpartum haemorrhage rates [92], and this may also be applicable at caesarean section [93].…”

An Overview on the Cause and Management of Postpartum Hemorrhage

“…Where Oxytocin and other utero tonic drugs including ergometrine, misoprostol degrades in response to heat or light, the efficacy of the drug diminishes making it less effective in the use of the management of PPH [24]. On contrary Carbetocin has met the requirement of the International Council for Harmonization (ICH) to be used in hot and humid climates (Zone IVA and B) for the period of two years at 30 °C and half a year at 40 °C [25]. Inpatient with elective C-section Carbetocin 100ug of IV, bolus should be preferred over continuous oxytocin infusion to prevent PPH [26].…”