Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth

Abstract

Objective: To determine the maximum tolerated dose (MTD) of carbetocin (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. Materials and methods: Carbetocin was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 μg carbetocin were assigned to blocks of three women according to the continual reassessment method (CRM). Results: All dosage groups consisted of three women, except those with 100 μg ( n=6) and 200 μg ( n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe abdominal pain (0), vomiting (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with blood loss ≥1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70–125 μg dose range. Four out of six cases with blood loss ≥1000 ml occurred in the 200 μg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 μg. All retained placentae were found in the group of 200 μg. Conclusion: The MTD was calculated to be at 200 μg carbetocin.