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. 2026 Sep 28;19(10):e70735. doi: 10.1111/cts.70735

The Effect of Carbetocin on Cardiac Repolarization: A Randomized, Placebo‐ and Positive‐Controlled QT/QTc Study in Healthy Adults

Daniël M Jonker 1,✉, Katie Barletta 1, Ekaterine Bagci 1, Kyle Raymond 1, Philippe Pinton 1
PMCID: PMC13617388  PMID: 42802704

ABSTRACT

Carbetocin is an oxytocin receptor agonist used for postpartum hemorrhage prevention. While oxytocin is known to transiently prolong the QT/QTc interval, robust QTc data for carbetocin are limited. Carbetocin is known to elevate HR, which can impact QTc analyses; thus, a dose that did not overly elevate HR was important to select. This randomized, placebo‐ and positive‐controlled trial evaluated the effect of a single intravenous infusion of a supratherapeutic dose (650 μg) of carbetocin over 45 min on cardiac repolarization in healthy adults (N = 42). Continuous cardiodynamic ECGs were recorded from 45 min before through 24 h after dosing. The primary endpoint was placebo‐corrected change from baseline in QT interval (ΔΔQTc) using the most appropriate heart rate (HR) correction method. The primary analysis was based on exposure‐response modeling of the relationship between carbetocin plasma concentrations and ΔΔQTc, to identify an effect ≥ 10 msec at the high clinical exposure. During intravenous infusion of carbetocin, the mean HR change from baseline reached a maximum of 16.7 bpm. Multiple correction methods for HR were assessed, and the placebo‐corrected, optimized, individualized heart rate–corrected QT interval (oQTcI) was found to be adequate. The estimated mean placebo‐corrected oQTcI change from baseline was 4.5 msec (90% CI: 3.4, 5.6) at the high clinical exposure level of 12.4 ng/mL following a single intravenous infusion of 867 μg/h carbetocin. Exposure‐response models for carbetocin established no predicted QTc prolongations of clinical or regulatory concern (≥ 10 msec) at the high clinical exposure level.

Trial Registration: ClinicalTrials.gov Registration: NCT05924321

Study Highlights

  • What Is the Current Knowledge on the Topic
    • ○
      Oxytocin and carbetocin are two of the most used treatment options for preventing postpartum hemorrhage. QT interval prolongation of clinical relevance has been reported for oxytocin and, due to the structural similarity between the two compounds, the possibility that carbetocin has a similar effect cannot be ruled out.
  • What Question Did This Study Address
    • ○
      To determine whether carbetocin prolongs the QT interval, and if so, to what extent, the effects of intravenous infusion of a supratherapeutic dose of carbetocin (650 μg) on cardiac repolarization were evaluated by continuously collected electrocardiograms (cardiodynamic ECGs) in healthy adults, with placebo control and active control (moxifloxacin). Carbetocin was administered over 45 min to reduce the risk of substantial heart rate increases (a commonly seen side effect, generally transient) interfering with the QT assessment. The study was designed to detect an effect of about ≥ 5 ms QT interval prolongation, if present.
  • What Does This Study Add to Our Knowledge
    • ○
      The estimated mean placebo‐corrected, optimized, individualized heart rate–corrected QT interval (oQTcI) change from baseline was 4.5 msec (90% CI: 3.4, 5.6) at the high clinical exposure level of 12.4 ng/mL following a single intravenous infusion of 867 μg/h carbetocin (650 μg over 45 min).
  • How Might This Change Clinical Pharmacology or Translational Science
    • ○
      The exposure‐response models for carbetocin established no predicted QTc prolongations of clinical or regulatory concern (≥ 10 msec) at the high clinical exposure level, providing important data related to the proarrhythmic risk for clinical practice.

1. Introduction

Carbetocin is an oxytocin receptor agonist, binding selectively to oxytocin receptors in uterine smooth muscle cells, stimulating rhythmic uterine contractions, increasing the frequency of existing contractions, and raising the uterine muscular tone [1, 2, 3]. It was first approved in 1997 and is now available in over 100 countries for use to prevent postpartum hemorrhage after cesarean section and vaginal delivery [4, 5]. Worldwide, adequate prevention of postpartum hemorrhage is important to reduce preventable maternal mortality [6].

Administration of carbetocin has been shown to reduce the need for additional oxytocics in cesarean delivery [2, 3, 7, 8]. Additionally, there is evidence showing the benefit of carbetocin over oxytocin to prevent postpartum hemorrhage and decrease blood loss after cesarean delivery [2, 9]. Carbetocin is administered intravenously or intramuscularly and has similar pharmacological properties to the endogenous hormone oxytocin, but is more selective for the oxytocin receptor and has a longer half‐life [1]. In addition, carbetocin is available in a formulation that is stable at room temperature, whereas oxytocin needs to be refrigerated during storage [10, 11].

Oxytocin is a potent vasoactive peptide that causes dose‐dependent changes in the circulatory system [12, 13]. Both carbetocin and oxytocin exert hemodynamic effects and decrease blood pressure through a direct vasodilatory effect that is accompanied by a compensatory increase in heart rate lasting several minutes following intravenous administration [14, 15, 16, 17]. Oxytocin is also known to transiently prolong the QT/QTc interval, which is noted in drug labeling [18, 19, 20]. In certain markets, carbetocin labels carry a note about the possible risk of QT interval prolongation due to its structural similarity to oxytocin. Because of the risk of drug‐induced cardiac arrhythmias that are associated with QT/QTc interval prolongation, characterization of the potential effects on electrocardiogram (ECG) parameters is considered important for drugs having systemic bioavailability [21].

Evaluation of QT interval change following carbetocin or oxytocin administration is complicated by an accompanying increased heart rate. The length of the QT interval decreases with increasing HR, and this effect needs to be separated from a direct effect of the drug on the QT interval duration. QT interval correction based on a narrow range of heart rates does not allow adequate evaluation when substantial changes in HR or autonomic state occur [22].

No dedicated and well‐designed QT studies have been published for oxytocin. For carbetocin, one study is described in an FDA Advisory Committee Briefing Information document, notably under a different therapeutic indication and with intranasal administration [23]. In that study, a QTcF elevation of 3.3 msec (90% confidence interval: 1.9, 4.7) was measured, which is under the threshold for clinical and regulatory concern. As the maximum exposure (Cmax) after intranasal administration was well below the Cmax following intravenous administration of 100 μg carbetocin as indicated for postpartum hemorrhage prevention, the magnitude of potential QT/QTc interval prolongation following intravenous administration remains uncertain.

Here, we describe a randomized, controlled, crossover study of the effect of intravenously infused carbetocin at a high clinical exposure on the QT/QTc interval, including baseline measurements over a wide range of heart rates.

2. Methods

2.1. Study Design

This was a single‐center, 2‐part (Part A and Part B), Phase 1 trial to evaluate the effect of carbetocin on cardiac repolarization in healthy participants. In Part A, a single intravenous dose of carbetocin was administered open‐label to evaluate whether changes in heart rate exceeded a predefined threshold prior to proceeding to Part B. Part B was a randomized, partially double‐blind (excluding moxifloxacin), placebo‐ and positive‐controlled, single‐dose, 3‐way crossover trial. Subjects participated in only one trial part.

The trial was conducted between May 26, 2023 (first screening visit) and September 21, 2023 (last participant completed) at Celerion (Tempe, AZ). The study protocol, participant information, and informed consent documents were reviewed and approved by the Advara Investigational Review Board Inc., Columbia, Maryland (approved May 9, 2023). The study was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. Written informed consent was obtained from all participants prior to any study activities.

2.2. Eligibility Criteria

Healthy participants were eligible for the study if they were between the ages of 18 and 45 years, had a body mass index (BMI) between 18.5 and 29.9 kg/m2, and had not used nicotine‐ or tobacco‐containing products for ≥ 3 months prior to first dose. Individuals were excluded from participating if they had any clinically significant disorders; major surgery within 4 weeks or minor surgery within 2 weeks prior to first dose; systolic blood pressure ≥ 130 mmHg or < 90 mmHg or diastolic blood pressure ≥ 80 mmHg or < 50 mmHg at screening; history or presence of clinically significant ECG findings, including heart rate < 45 bpm or > 100 bpm, QTcF ≥ 450 msec (males) or ≥ 460 (females), QRS segment ≥ 110 msec, or PR segment ≥ 200 msec; or a history of risk factors for Torsade de Pointes or other significant cardiac disorders. Individuals were excluded if they were taking any prescription or nonprescription medication within 14 days before the first dose; any vitamins, minerals, plant‐derived supplements, or omega‐3 fish oils within 7 days before the first dose; any oral or transdermal hormonal contraceptives, vaginal ring, or hormone‐eluting intrauterine device within 1 month before screening; transdermal implant within 3 months before screening; depot injection within 10 months before screening; corticosteroids or anabolic steroids within 30 days before screening; or any medications or supplements known to alter drug pharmacokinetics.

Females of childbearing potential and non‐vasectomized males were required to use effective contraception during the study.

2.3. Randomization

Part A was single‐arm and not randomized. For Part B, participants were assigned a unique, computer‐generated randomization number (block size 6) according to William's design for the sequence of treatments to receive the 3 trial treatments in 1 of 6 treatment sequences (3 = carbetocin; 4 = placebo; 5 = moxifloxacin): 345, 435, 534, 543, 453, and 354. Participants and administering staff were blind to the treatment sequence allocation.

2.4. Interventions

In Part A, the effect of a single IV infusion of 650 μg carbetocin over 45 min on heart rate was evaluated. This dosing regimen was anticipated to result in supratherapeutic carbetocin plasma concentrations based on predictions from a PK model for an unpublished PK study evaluating a 1‐min IV infusion of 100 μg carbetocin in healthy women. If the mean change in heart rate exceeded 20 bpm at any time point, a lower dose of 433 μg over 45 min was to be evaluated to reduce the risk of interference with the QT/QTc interval assessment.

In Part B, participants received 3 treatments in a crossover design with randomized sequence: A single infusion of carbetocin (650 μg over 45 min) as determined in Part A; a single IV infusion of matching placebo; and a single IV infusion of matching placebo with a single, open‐label oral dose of moxifloxacin hydrochloride, 400 mg (Figure 1). All participants were scheduled to receive a single dose of all 3 treatments in a crossover design with washout periods of at least 5 days between each trial dose administration. Cardiodynamic ECGs were recorded using 12‐lead Holter monitors and were used to assess the effect of carbetocin infusion on heart rate (HR)–corrected QT interval (QTc) relative to placebo, with an open‐label comparison to moxifloxacin (positive control) [24, 25, 26].

FIGURE 1.

FIGURE 1

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Trial Design. Part B evaluated the effect of carbetocin on QTc (heart rate‐corrected QTc interval) versus placebo, with an open‐label comparison to moxifloxacin (positive control). Participants received the 3 trial treatments in 1 of 6 treatment sequences (3 = carbetocin; 4 = placebo; 5 = moxifloxacin): 345, 435, 534, 543, 453, or 354. Abbreviations: IV, intravenous.

Participants rested quietly in the supine position for at least 10 min prior to each 12‐lead safety ECG and throughout the duration of the reading. ECG data were extracted before the start of infusion (45, 30, and 15 min) and after the start of infusion (15, 30, 45, 55, 70, 90, 120, and 240 min). In treatment Period 1 only, cardiodynamic ECG extractions were performed on Day −1, time‐matched (±10 min) to the anticipated collection times relative to the start of infusion on Day 1. In each treatment period, cardiodynamic ECGs and PK blood samples for carbetocin, matching placebo, and moxifloxacin treatment (as applicable) were collected on Day 1 prior to start of infusion and for 24 h following SOI (nominally at 15, 30, 45, 55, 70, 90, 120, and 240 min).

2.5. Endpoints

In Part A, the primary endpoint was the observed HR values and change from baseline of HR from 45 min before through 4 h after carbetocin administration.

In Part B, the primary endpoint was the placebo‐corrected change in HR‐corrected QT interval (ΔΔQTc) using the most appropriate HR correction method [22, 27]. If the mean change in HR was > 10 bpm in Part B, alternative methods for QTc correction were tested for their ability to remove HR dependence, including a method utilizing drug‐free baseline data over a wide range of HRs (Figure S1). Cardiodynamic ECGs were recorded using a continuous 12‐lead Holter monitor the day before infusion (Day −1) and on the day of infusion from 45 min before through 24 h following treatment administration.

In Part B, secondary endpoints for carbetocin administration included: Absolute values, change from baseline, and placebo‐corrected change from baseline in HR, PR, RR, QRS, and QTcF; abnormalities in T‐wave morphology and pathologic U‐waves; and pharmacokinetic parameters. Additionally, placebo‐corrected change from baseline in HR‐corrected QT interval (ΔΔQTc) following moxifloxacin was assessed.

In both parts, treatment‐emergent adverse events, vital signs, 12‐lead ECGs, and clinical chemistry, hematology, and urinalysis parameters were collected to assess safety and tolerability.

2.6. Statistical Analyses

Five HR correction methods were investigated for their ability to remove the HR effect on the QT interval (see Table S1 for details). For each method, the relationship between QTc and RR interval was evaluated for baseline and/or placebo data (all QT‐RR data from Day −1 in the first treatment period and/or placebo). Briefly, the HR correction methods differed in how the slope of the relationship between QT and RR was calculated and whether the estimate was based on population data or individual data. QT and RR data were log‐transformed, and HR correction was applied to drug‐free QT‐RR data at baseline. The adequacy of each HR correction was determined by the independent relationship between the HR‐corrected QT interval and the RR interval using a linear mixed‐effects model. The linear mixed‐effects slope was estimated for each correction method and each individual using data from Day −1 baseline, and the average sum of squared individual slopes was calculated using data from the placebo treatment period. Further, the observed and predicted QTc‐RR relationships were plotted.

The method ultimately selected for HR correction in this study was the placebo‐corrected, optimized, individualized heart rate–corrected QT interval (oQTcI) that was calculated from all QT–RR data pairs from Day −1. The QT–RR pairs from each participant were then used for that participant's individual correction coefficient, which was derived from a linear regression model.

After confirming the most adequate method of QT interval correction, the relationship between time‐matched ∆∆QTc and carbetocin concentrations was examined by linear mixed‐effects models. The mixed‐effects models with ∆QTc as the dependent variable included time‐matched concentrations of carbetocin as the explanatory variable (0 for placebo), treatment (carbetocin = 1, placebo = 0) and time (i.e., postdose time points) as fixed effects, centered‐baseline QTc (i.e., individual baseline QTc minus the arithmetic mean baseline QTc of all participants in the same period) as an additional covariate, and subject as a random effect on both intercept and slope terms.

Categorical data were summarized using frequency (n) and percentage (n/N*100). Continuous data were presented for observed values and change from baseline. Baseline HR was the average value of 3 predose measurements within 1 h before drug administration. For each individual participant, each change in HR‐corrected QT interval value was calculated as the average of the ECG measurements during treatment minus the average of the ECG measurements at baseline. Models were used to estimate the ∆HR at each time point, as appropriate. The linear mixed‐effect models included the fixed categorical effects of time point. The estimated mean ∆HRs to each postdose time point and corresponding 90% CI were calculated.

3. Results

3.1. Demographics and Baseline Characteristics

A total of 7 participants enrolled in Part A, and 42 participants enrolled in Part B. Two participants in Part B discontinued due to an adverse event (one discontinued during Period 1, and one discontinued during Period 3). In Part A, the mean (standard deviation [SD]) age was 34 (6) years, 71% were female, 100% were White, and mean (SD) BMI was 26 (3) kg/m2. In Part B, the mean (SD) age of the randomized participants was 35 (7) years, 50% were female, 88% were White, and mean (SD) BMI was 26 (2) kg/m2.

3.2. Part A—Heart Rate Analysis

After the start of the 45‐min infusion, the mean HR increased, peaking at 18 bpm above baseline at 15 min after the start of infusion. As the protocol‐specified threshold of 20 bpm was not exceeded, the trial proceeded to Part B without a reduction in carbetocin infusion rate.

3.3. Part B—Carbetocin Pharmacokinetics

Carbetocin plasma concentrations matched prospectively predicted concentrations closely (Figure 2). Maximum carbetocin geometric mean plasma concentrations of 19.5 ng/mL were observed at the end of infusion and exceeded by 1.6‐fold the high clinical exposure level of 12.4 ng/mL (from a 1‐min infusion of 100 μg carbetocin); therefore, the exposure levels of carbetocin were adequate for concentration‐QTc evaluation.

FIGURE 2.

FIGURE 2

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Plasma concentrations of carbetocin following a single infusion of 867 μg/h carbetocin. The predicted data are derived from a pharmacokinetic (PK) model for an unpublished PK study evaluating a 1‐min intravenous infusion of 100 μg carbetocin in healthy women (Ferring data on file).

3.4. Part B—QTc Analysis

The change in HR over time following carbetocin administration is shown in Figure 3. The estimated placebo‐adjusted mean change from baseline in HR peaked at 15.5 bpm at 15 min after the start of carbetocin infusion. Following carbetocin infusion, all participants had HR values < 100 bpm, except for 2 participants who had HR values > 100 bpm at 15, 30, and 45 m after starting carbetocin.

FIGURE 3.

FIGURE 3

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Change in HR over time (Part B). Data are shown as mean (90% confidence interval).

Because a maximum increase in HR > 10 bpm was seen during the first 15 min after the start of infusion, and due to the concern about the impact of HR elevation on interpretation of the QTc, the performance of five distinct HR correction methods was evaluated (described in Figure S1). The pre‐specified criteria for choosing the primary correction method indicated that using pooled ECG data from each participant's baseline supine resting time points (QTcS) had the best fit; however, this method used baseline data within a fraction of the entire HR range from Day −1 data. When deriving QTcS, the range of on‐treatment HR was covered by the Day −1 range of HR in only 4.9% of participants, which may have negatively impacted the accuracy of the correction method. Among the alternative HR correction methods explored, the HR coverage was high (97.6%) when using ECG data from each participant's full baseline (24‐h) recordings for that participant's individual correction (oQTcI) and thus was considered to be more relevant than the other correction methods that were evaluated (Figure S1). Correction of baseline HR values using oQTcI showed a regression slope of 0.0082, indicating adequate correction (Figure 4).

FIGURE 4.

FIGURE 4

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Optimized QTcI versus RR interval from Day 1 of Carbetocin Treatment. The slope of the regression line is 0.0082.

The change in oQTcI over time is shown in Figure 5. The estimated placebo‐adjusted mean change from baseline in oQTcI after the start of carbetocin infusion ranged from 9.9 msec at 15 min after infusion to −1.4 msec at 4 h (Table 1). Individual QT/QTc values were ≤ 450 msec and changes from baseline were ≤ 30 msec for all participants after receiving carbetocin.

FIGURE 5.

FIGURE 5

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Central Tendency Analysis of Change in Optimized QTcI. Data are shown as estimated mean (90% confidence interval).

TABLE 1.

Placebo‐adjusted mean change from baseline in oQTcI.

Time since start of infusion Carbetocin Moxifloxacin
Estimated ΔΔoQTcI 90% CI Estimated ΔΔoQTcI 90% CI
15 min 9.9 8.0, 11.8 0.3 −1.6, 2.3
30 min 6.3 4.7, 7.8 −0.5 −2.0, 1.0
45 min 5.2 3.3, 7.1 5.1 3.2, 6.7
55 min 3.3 1.3, 5.2 8.0 6.1, 10.0
70 min 1.1 −0.7, 2.8 9.0 7.3, 10.8
90 min −0.5 −2.2, 1.2 9.8 8.1, 11.5
120 min 0.7 1.3, 2.6 11.1 9.1, 13.0
3 h −0.7 −2.4, 1.0 12.9 11.2, 14.6
4 h −1.4 −3.2, 0.5 10.8 8.9, 12.6
6.5 h −0.7 −2.7, 1.4 8.3 6.2, 10.4
8 h −0.6 −2.5, 1.3 8.4 6.5, 10.4
12 h 0.7 −1.4, 2.8 6.7 4.6, 8.8
24 h 1.0 −0.8, 2.7 7.2 5.4, 8.9
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Note: Linear mixed model with the average of the three triplicate oQTcI measurements taken as the dependent variable and centered baseline oQTcI as a covariate, period and sequence as factors, and a treatment by time since start of infusion (minutes) interaction term.

Abbreviation: CI, confidence interval.

A scatterplot of placebo‐corrected change from baseline oQTcI versus carbetocin concentrations is shown in Figure 6a. Using the model‐predicted, placebo‐corrected change from baseline in oQTcI, following a single IV infusion of 650 μg carbetocin over 45 m, the estimated mean ΔΔoQTcI (90% CI) was 4.5 (3.4, 5.6) msec at the high clinical exposure level of 12.4 ng/mL (Figure 6b). This ΔΔoQTcI was not significant and rules out a QT interval prolongation of ≥ 10 msec. The slope estimate for the relationship between concentration and oQTcI was 0.4 and was statistically significantly higher than zero (p < 0.0001).

FIGURE 6.

FIGURE 6

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(top) Time‐matched, Placebo‐corrected, Baseline‐adjusted oQTcI Values Versus Carbetocin Concentration. Shaded area shows the 95% confidence interval. (bottom) Estimated placebo‐corrected, optimized, individualized heart rate–corrected QT interval (ΔΔoQTcI) versus time‐matched plasma carbetocin concentration. Shaded area shows the 90% CI of the estimated relationship.

Because the maximum HR mean change from baseline was 16.7 bpm at 15 min after carbetocin infusion, a sensitivity analysis was performed using RR interval correction [28]. The results of the sensitivity analysis were consistent with the results of the main analysis. The estimated mean ΔΔoQTcI (90% CI) was 4.5 msec (3.4, 5.5) at the high clinical exposure level of 12.4 ng/mL. This sensitivity analysis ruled out any artifact from QT‐RR hysteresis in the results of the HR‐corrected QTc interval.

The predicted ΔΔQTcF at the geometric mean peak moxifloxacin concentration (1.9 μg/mL) was 13.0 ms (90% CI: 11.5, 14.4). Because the slope of the C‐QTcF relationship was statistically significant (p ≤ 0.05) and the lower bound of the 2‐sided 90% CI of the predicted effect was > 5 msec, assay sensitivity was demonstrated.

Finally, carbetocin at the studied doses had no clinically relevant effect on cardiac conduction (i.e., PR and QRS intervals).

3.5. Safety

A single 650‐μg IV infusion of carbetocin was generally safe and well tolerated. In Parts A and B, no serious or severe TEAEs were reported. TEAEs were reported in Part A by 5/7 (71%) participants receiving carbetocin, and in Part B by 25/42 (61%) participants receiving carbetocin, 10/41 (24%) receiving placebo, and 12/41 (29%) receiving moxifloxacin. In Part B, 2 participants discontinued due to an AE (moderate sinus tachycardia following carbetocin, considered reasonably possibly related to the study drug; increased AST following placebo). In Part B, there was one AE of special interest of a QT interval increase from baseline > 60 msec following moxifloxacin.

The most frequently reported TEAEs in Part A (≥ 2 participants) were headache (3/7 [43%]) and dizziness (2/7 [29%]); in Part B, the most frequently reported TEAEs (≥ 10% of group) were flushing (20/41 [49%] for carbetocin, 0 for placebo, and 0 for moxifloxacin), palpitations (13/41 [32%], 0, and 1/41 [2%], respectively); and headache (8/41 [20%], 2/41 [5%], and 2/41 [5%], respectively). A list of all TEAEs reported by study participants can be found in Table S2.

4. Discussion

In this QT/QTc study of carbetocin administered by infusion in healthy participants, the exposure–response model established the absence of a QTc prolongation of clinical or regulatory concern (≥ 10 msec) at the high clinical exposure. These findings are consistent with a prior study of intranasal carbetocin in healthy adults, in which 3.2 mg intranasal carbetocin was estimated to result in 3.3 msec (90% CI: 1.9, 4.7) QTc interval prolongation, which was concluded to be not clinically meaningful [23]. In line with our study result, the slope of the concentration‐QTc relationship was statistically significantly higher than zero. The highly controlled design of the present study permitted application of an individualized QT correction method using QT–RR pairs from each participant's full 24‐h baseline recording (QTcI), facilitating distinction between QT changes attributable to heart rate increases and those potentially related to a direct drug effect. The observation of the central tendency analysis exceeding the 10 ms threshold at a single time point at the end of infusion may be related to rapid heart rate changes that occurred, which could not be fully accounted for despite all efforts made to correct for heart rate changes by various correction methods and accounting for potential QT‐RR hysteresis. We do not believe that this observation is of concern based on the concentration‐response analyses by model‐free and model fitting approaches (Figure 6).

Oxytocin is reported to induce an increase in QT interval, possibly demonstrating a class effect [18, 19]. A randomized, double‐blind trial of 40 healthy pregnant women undergoing elective cesarean delivery showed that a 1‐min IV infusion of oxytocin or carbetocin following delivery induced modest variability in the QT interval (−1.9 ms to 10.4 ms, corrected for HR using the Framingham method), though the values were within normal range [18]. Although for a different indication, a study of 38 women undergoing surgically induced abortion under general anesthesia showed a QT interval prolongation of 41 ms (corrected for HR using Fridericia's formula) at 1 min after IV bolus of oxytocin [19]. An observational study of 20 women undergoing elective cesarean delivery showed a maximum QT interval prolongation of 18 ms at 7 min after carbetocin IV bolus administration [29].

The pharmacological effects of oxytocic agents also include a transient decrease in blood pressure and a compensatory transient increase in heart rate. Extensive experience with carbetocin during both development and the postmarketing period, when used for the intended indication, is in line with its known safety profile. The known electrocardiac and hemodynamic effects of carbetocin appear to be clinically safe and tolerable, as there are years of extensive experience using carbetocin as a uterotonic agent, especially in the prevention and management of postpartum hemorrhage following cesarean delivery [2, 3, 4, 5, 7, 8, 9, 30, 31, 32, 33, 34].

A limitation of prior published studies is that the QT interval was corrected for HR changes using fixed methods, which are not adequate in the face of substantial HR changes [22]. Furthermore, assessment of drug‐related QTc effects in the peripartum obstetric setting is inherently challenging due to dynamic physiologic changes during labor and the immediate postpartum period (e.g., heart rate variability, autonomic tone, hemodynamics, and electrolyte shifts) that can independently influence ventricular repolarization [35, 36]. In addition, the frequent use of multiple concomitant peri‐delivery medications—some with known or potential QT‐prolonging effects—further limits the interpretability of small QTc changes and attribution to a single agent [37]. The multifactorial and complex nature of postpartum adverse events, as well as cardiac physiology, potentially influenced by surgery, anesthesia, or other interventions during the management of the third stage of labor, complicates the establishment of a clear causal relationship between observed adverse events and drug(s) administered during labor and delivery [38, 39].

A major strength of this study is the controlled design and robust evaluation of multiple methods of HR correction. This study is further strengthened by performing a sensitivity analysis to determine if the lag with which a change in QT interval duration trailed an HR change, known as the QT‐RR hysteresis, affected the results [40]. An RR interval correction sensitivity analysis was performed and supported results from the main analysis. This sensitivity analysis supported the conclusion that QT‐RR hysteresis was insignificant. Furthermore, the inclusion of moxifloxacin as a positive control confirmed assay sensitivity.

A single 650‐μg IV infusion of carbetocin over 45 min was generally safe and well tolerated in this study. Increased HR after carbetocin or oxytocin administration is a known effect [14, 15, 16, 30, 31, 41]. Continuous infusion to achieve stable HR has been proposed previously [42, 43, 44, 45]. In the present study, use of a 45‐min infusion of 650 μg carbetocin resulted in a Cmax that exceeded the high clinical exposure for a 1‐min infusion of 100 μg carbetocin. The 45‐min infusion induced a transient increase in HR, with HR gradually decreasing from 15 min after administration and onwards. Palpitations observed after carbetocin administration are plausibly linked to its known hemodynamic effects. The timing and nature of these events support a reasonable association with carbetocin. Considering the known cardiac effects and the clinical settings in which carbetocin is administered (i.e., close patient monitoring), the event ‘palpitations’ does not change the overall benefit–risk profile of carbetocin.

While this study was able to assess the QTc effect of carbetocin in healthy females and males 18–45 years of age, the study was not conducted postpartum in females in whom physiological changes and effects of comedications would interfere with the safety assessment. It is unlikely that biological sex would introduce a large difference in the QT response that is not explained by exposure. Subgroup analysis by sex is not a regulatory expectation if the primary analysis is negative. The use of a supratherapeutic dose of carbetocin (650 μg IV over 45 min), which is a higher concentration and slower delivery than in typical clinical dosing (usually 100 μg IV over 1 min, or IM), was considered appropriate for cardiac safety assessment but may not reflect outcomes observed after administration in routine clinical practice. However, drugs that prolong the QTc interval due to direct ion channel effects do so in an exposure‐dependent fashion, and QTc prolongation does not dissipate while plasma concentrations remain constant.

A limitation of this study is that the slower infusion of carbetocin than in clinical practice did not fully mitigate the HR increase. However, the observed HR increase was compensated for through multiple means, including evaluation of various HR correction methods, collection of Day −1 ECG data, and assessment of QT‐RR hysteresis.

5. Conclusion

In this randomized, controlled crossover study, intravenous carbetocin at supratherapeutic exposure did not result in clinically relevant QT/QTc interval prolongation in healthy adults. The use of optimized individualized heart rate correction methods ensured robust assessment despite transient heart rate increases. All observed QT/QTc values remained within regulatory safety thresholds, and exposure‐response modeling confirmed the absence of QTc prolongation of clinical concern. Carbetocin was generally safe and well tolerated, with adverse events consistent with its known pharmacological profile and no serious or severe events reported. These findings support the safety of carbetocin related to the QT interval and provide important data related to the proarrhythmic risk for clinicians who use it in routine clinical practice.

Author Contributions

All authors wrote the manuscript, designed the research, and analyzed the data.

Funding

The authors have nothing to report.

Disclosure

D.M.J., E.B., and K.R. are employees of Ferring Pharmaceuticals A/S. K.B. and P.P. were employees of Ferring Pharmaceuticals at the time of the study. P.P. is a shareholder and the CEO of Shiroito Co. Ltd., holds stocks or stock options in Takeda Pharmaceutical, and serves on the board of directors of PharmaBiome.

Supporting information

Figure S1: Heart rate coverage using supine Day −1 (before treatment) HR (left panel, dark blue) or ambulant Day −1 HR (right panel, cyan) relative to the on‐treatment HR range for carbetocin (red). Each line represents one study participant.

Table S1: Heart Rate Correction Methods.

Table S2: Individual TEAEs Reported for Each Participant.

CTS-19-e70735-s001.docx (722.4KB, docx)

Acknowledgments

Medical writing and editorial support were provided by AIM Biomedical LLC (Clayton, MO) and sponsored by Ferring Pharmaceuticals A/S.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1: Heart rate coverage using supine Day −1 (before treatment) HR (left panel, dark blue) or ambulant Day −1 HR (right panel, cyan) relative to the on‐treatment HR range for carbetocin (red). Each line represents one study participant.

Table S1: Heart Rate Correction Methods.

Table S2: Individual TEAEs Reported for Each Participant.

CTS-19-e70735-s001.docx (722.4KB, docx)

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