product monograph pabal - obstetrikk.noproduct monograph pabal® (carbetocin 100 micrograms/ml...

PRODUCT MONOGRAPH

Pabal®

(Carbetocin 100 micrograms/mL solution for injection)

Carbetocin 100 micrograms/mL solution for injection is marketed by Ferring B.V. and/ or one of its affiliates, dependent on country, with one of the following registered

trademarks: PABAL®, DURATOCIN®, LONACTENE®, LONACTENE RT® and DURATOBAL®

ABBREVIATIONS ...............................................................................................4

TABLES ..............................................................................................................5

INTRODUCTION .................................................................................................8

FERRING AND OBSTETRICS ...........................................................................10

CHAPTER I .......................................................................................................11

1.1 DEFINITION OF POSTPARTUM HAEMORRHAGE .................................11

1.2 INCIDENCE OF POSTPARTUM HAEMORRHAGE ..................................12

1.3 IMPACT OF POSTPARTUM HAEMORRHAGE .........................................13

1.4 AETIOLOGY OF POSTPARTUM HAEMORRHAGE ...................................14

1.4.1 Uterine atony .................................................................................15

1.4.2 Uterine, cervical or vaginal trauma ..............................................16

1.4.3 Retained placental tissue .............................................................16

1.4.4 Pre-existing or acquired coagulopathy ........................................16

1.5 DIAGNOSIS OF POSTPARTUM HAEMORRHAGE ...................................17

CHAPTER II ......................................................................................................19

2.1 PREVENTION OF POSTPARTUM HAEMORRHAGE ...............................19

2.1.1 Guidelines on the management of the third stage of labour ......19

2.1.2 Uterotonic agents ..........................................................................25

2.1.3 Cord clamping ...............................................................................30

2.1.4 Controlled cord traction ................................................................30

2.2 TREATMENT OF POSTPARTUM HAEMORRHAGE.................................31

2.2.1 Uterotonic agents ..........................................................................32

2.2.2 Prothrombotic agents ...................................................................33

2.2.3 Non-pharmacological interventions: balloon devices and surgery ......................................................................34

CHAPTER III .....................................................................................................37

3.1 RATIONALE FOR THE DEVELOPMENT OF CARBETOCIN AND ITS NEW HEAT-STABLE FORMULATION ......................................37

3.1.1 Need for a uterotonic agent with consistent dosage and method of administration .........................................37

3.1.2 A good safety profile is the key consideration for any uterotonic agent ........................................37

3.1.3 Alternative uterotonic agents to oxytocin for PPH prevention have shown some limitations ............................39

3.1.4 Need to overcome refrigerated storage conditions .........................................................................40

3.2 CARBETOCIN PROPERTIES ...................................................................40

3.2.1 Indications, clinical properties and guideline recommendations .........................................................40

3.2.2 Room temperature-stable formulation ........................................41

3.2.3 Potency at the vasopressin V2 receptor ........................................42

CONTENTS

3.3 MECHANISM OF ACTION ................................................................................................. 44

3.4 PRE-CLINICAL STUDIES ................................................................................................. 45

3.5 CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS OF CARBETOCIN ....................................................................... 46

3.5.1 Overview of the clinical studies .............................................................................. 46

3.5.2 Pharmacokinetic studies ........................................................................................ 48

3.5.3 Pharmacodynamic studies ..................................................................................... 51

3.5.4 Dose-ranging studies .............................................................................................. 52

CHAPTER IV ...............................................................................................................................57

4.1 CLINICAL EFFICACY AND SAFETY OF CARBETOCIN ..................................................... 57

4.1.1 Overview of the clinical studies .............................................................................. 57

4.2 EFFICACY AND SAFETY OF CARBETOCIN VERSUS PLACEBO ...................................... 68

4.2.1 Barton et al. 1996 .................................................................................................... 68

4.3 EFFICACY AND SAFETY OF CARBETOCIN VERSUS OXYTOCIN ..................................... 70

4.3.1 Boucher et al. 1998 .................................................................................................. 70

4.3.2 Dansereau et al. 1999 .............................................................................................. 73

4.3.3 Boucher et al. 2004 ................................................................................................. 74

4.3.4 Borruto et al. 2009 .................................................................................................. 76

4.3.5 Attilakos et al. 2010 ................................................................................................. 78

4.3.6 Reyes et al. 2011 ...................................................................................................... 80

4.3.7 Moertl et al. 2011 ..................................................................................................... 82

4.3.8 Rosseland et al. 2013 .............................................................................................. 87

4.4 EFFICACY AND SAFETY OF CARBETOCIN VERSUS SYNTOMETRINE ........................... 91

4.4.1 Leung et al. 2006 ..................................................................................................... 91

4.4.2 Nirmala et al. 2009 .................................................................................................. 94

4.4.3 Su et al. 2009 ........................................................................................................... 95

4.4.4 Askar et al. 2011 ...................................................................................................... 97

4.5 EFFICACY AND SAFETY OF CARBETOCIN VERSUS MISOPROSTOL PLUS OXYTOCIN ...................................................................... 99

4.5.1 Elgafor el Sharkwy 2013 ......................................................................................... 99

CHAPTER V ..............................................................................................................................102

SUMMARY OF PRODUCT CHARACTERISTICS .................................................................... 102

SUMMARY OF KEY POINTS ....................................................................................................108

CONCLUSIONS ........................................................................................................................109

REFERENCES ..........................................................................................................................111

ACTH ..........................................................Adrenocorticotrophic hormone

ACOG .......................................................... American College of Obstetricians and Gynecologists

Alpha-HL...................................................Distribution half-life

AUC0–inf ....................................................... Area under the plasma concentration versus time curve from time 0 to infinity

Beta-HL .....................................................Elimination half-life

BMI.............................................................Body mass index

CCT .............................................................Controlled cord traction

CI ................................................................Confidence interval

Clr ...............................................................Total renal clearance

Clt ...............................................................Total body clearance

Cmax .............................................................Maximum concentration

DLAE ..........................................................Dose-limiting adverse event

EC50 ............................................................50% of the maximal effective concentration

F .................................................................Bioavailability

FIGO ........................................................... International Federation of Gynecology and Obstetrics

IM ............................................................... Intramuscular

IV ................................................................ Intravenous

MTD ...........................................................Maximum tolerated dose

OR ..............................................................Odds ratio

PGE ............................................................Prostaglandin E

PGF2α .........................................................Prostaglandin F2α

PPH ............................................................Postpartum haemorrhage

RCOG.......................................................... Royal College of Obstetricians and Gynaecologists

rFVIIa .........................................................Recombinant activated factor VII alpha

RR ..............................................................Relative risk

SAP ............................................................Systolic arterial pressure

SD ...............................................................Standard deviation

SOGC .......................................................... Society of Obstetricians and Gynaecologists of Canada

Tmax .............................................................Time to peak concentration

UN ..............................................................United Nations

WHO ...........................................................World Health Organization

ABBREVIATIONS

4

Table Title Page

Definition of postpartum haemorrhage

1 Definition of postpartum haemorrhage according to various international and national guidelines 12

Aetiology of postpartum haemorrhage

2 Risk factors associated with the four principal causes of primary postpartum haemorrhage 15

Guidelines on the management of the third stage of labour

3 International and country recommendations on prevention of postpartum haemorrhage 20

Oxytocin administration modalities and dosages

4 Oxytocin has been used with a wide range of administration methods, dosing and timing 27

Treatment of postpartum haemorrhage

5 International and country recommendations for the treatment of postpartum haemorrhage 31

Overview of the carbetocin clinical studies

6 Inclusion/exclusion criteria for the two pharmacokinetic studies 47

7 Inclusion/exclusion criteria for the three pharmacodynamic studies 48

Carbetocin pharmacokinetic study: Sweeney et al. 1990

8 Key pharmacokinetic parameters for carbetocin in non-pregnant women 49

Room temperature-stable formulation carbetocin bioavailability study: FE 992097 000146

9 Key pharmacokinetic parameters for room temperature-stable carbetocin in non-pregnant women 50

Carbetocin dose-finding studies

Hunter et al. 1992

10 Uterine tetany without significant side effects was observed in 11 out of 15 pregnant women administered a total intravenous dose of carbetocin ranging 8–30 mcg 52

CLN 6.3.5

11 Women who received a starting dose of 60 mcg or lower required additional dose administration 53

12 No women who received a starting dose of 60 mcg or lower achieved tetanic uterine contraction without additional uterotonics 54

13 Few adverse events were reported 54

van Dongen et al. 1998

14 Maximum-tolerated dose for carbetocin was estimated to be 200 mcg, based on serious adverse events, dose-limiting adverse events and interventions 55

15 Highest blood loss was seen at the lowest and highest carbetocin doses tested 55

TABLES

5

Table Title Page

Overview of the carbetocin clinical studies

16Trial designs for all 14 studies comparing carbetocin with other uterotonic agents for the prevention of postpartum haemorrhage in women undergoing caesarean or vaginal delivery

57

17Dosing protocols and outcomes for all 14 trials comparing carbetocin with other uterotonic agents for the prevention of postpartum haemorrhage in women undergoing caesarean or vaginal deliveries

62

Efficacy and safety of carbetocin versus placebo

Barton et al. 1996

18 Nausea and flushing were more commonly reported in the carbetocin group than in the placebo group 70

Efficacy and safety of carbetocin versus oxytocin

Boucher et al. 1998

19 Adverse events were comparable between carbetocin and oxytocin 72

Dansereau et al. 1999


Boucher et al. 2004


Borruto et al. 2009

22 Significantly fewer women in the carbetocin group required uterotonic medication or massage, compared with the oxytocin group 77


Attilakos et al. 2010

24 Significantly fewer women in the carbetocin group required additional uterotonics, compared with women in the oxytocin group 79


Reyes et al. 2011

26 Carbetocin and oxytocin led to similar outcomes in women with pre-eclampsia 81

27 Adverse events in women with pre-eclampsia were comparable between carbetocin and oxytocin 81

Moertl et al. 2011

28 Changes in heart rate and rebound bradycardia were smaller and slightly delayed in women treated with carbetocin compared with women treated with oxytocin 82


Rosseland et al. 2013


6

Table Title Page

Efficacy and safety of carbetocin versus syntometrine

Leung et al. 2006

31 Haemoglobin concentrations before and 48 hours after delivery were similar between carbetocin and syntometrine 92

32 Volume of blood loss and incidence of postpartum haemorrhage were similar between carbetocin and syntometrine 92

33 Lower rates of nausea, vomiting and hypertension were reported in the carbetocin group than in the syntometrine group 93

Nirmala et al. 2009

34Compared with women treated with syntometrine, the women who received carbetocin showed significantly lower blood loss and a decreased reduction in haemoglobin levels

94

35 Adverse events were comparable between carbetocin and syntometrine 95

Su et al. 2009

36 Need for additional uterotonics and the mean blood loss were comparable between carbetocin and syntometrine women 96

37 Rates of nausea and vomiting were significantly elevated in the syntometrine group compared with the carbetocin group 97

Askar et al. 2011

38 Women treated with carbetocin had a significantly lower mean blood loss and a reduced drop in haemoglobin levels compared with those treated with syntometrine 98

39 Lower rates of nausea, vomiting and hypertension were reported in the carbetocin group than in the syntometrine group 99

Efficacy and safety of carbetocin versus misoprostol plus oxytocin

Elgafor el Sharkwy 2013

40 Primary and secondary outcomes were comparable between the carbetocin and misoprostol plus oxytocin groups 100

41 Shivering and fever were more common in the misoprostol plus oxytocin group than in the carbetocin group 100

Summary of Product Characteristics

42 Adverse events observed with carbetocin during the clinical trials 105

7

Across the world, postpartum haemorrhage (PPH) has claimed the lives of 480,000 women and was the single largest cause of maternal mortality and morbidity between 2003 and 2009, based on a World Health Organization (WHO) analysis that was conducted in 2014. The problem has been shown to be particularly acute in the developing world, where 20% of maternal deaths were attributed to PPH compared with 8% in developed regions.1 PPH accounts for a large proportion of severe maternal morbidity.2 For example, complications such as blood transfusion, hysterectomy and uterine artery ligation have been observed in women with PPH resulting from uterine atony.3 PPH can also lead to fatigue and anaemia, which can impair the initial bonding of mother and child.4

Risk factors for PPH and severe PPH, such as prolonged third stage of labour (defined as the time from the birth of the baby to the expulsion of the placenta and membranes),5 multiple pregnancy, previous PPH or existing coagulopathies have been identified.6–9 However, most cases of PPH are associated with no identifiable cause,10,11 and several national and international guidelines recommend active management of the third stage of labour for all deliveries, irrespective of risk status.10,12–16 Besides alerting clinicians to apply the key principles of active management, such as the administration of a prophylactic uterotonic after the delivery of a baby (see Section 2.1.1),10 the identification of women who may present with PPH also enables clinicians to prepare and plan for the delivery; for example, registering the woman to deliver in a tertiary hospital equipped with intensive care facilities and access to specialist services, establishing intravenous (IV) access and ensuring the availability of cross-matched blood group.17,18

The most frequent cause of PPH is postpartum uterine atony;19–22 consequently, effective active management of the third stage of labour is widely recommended as a key factor in preventing PPH.23 Active management with uterotonic agents, primarily with oxytocin, has proven effective in reducing the incidence of PPH.5 Other uterotonics are: carbetocin, ergometrine, intramuscular (IM) prostaglandin E2 (PGE2) or oral misoprostol.5 The use of ergometrine, IM PGE2 or oral misoprostol has been shown to reduce the incidence of PPH compared with placebo or no treatment;24–27 however, ergometrine and oral misoprostol demonstrated inferiority to oxytocin in preventing PPH and were associated with significantly more side effects.27–29 Although there is a paucity of studies comparing PGE2 with oxytocin, the available data suggest that both agents are equally effective in preventing blood loss, but that the prostaglandin has more side effects.27,30

Oxytocin is the principal medication used to prevent uterine atony and PPH.23 Nevertheless, different dosages and methods of administration, including IV and IM injections, are recommended in the label from some European countries (UK, France, Italy, Spain and Germany).31–35 Moreover, numerous modalities and dosages have been used in clinical trials (see Section 2.1.2.1)36–43 and are also recommended by several major guidelines.10,11,13,14,44 These include prolonged IV infusions (such as 4, 6, 8 and 16 hours).13,37–41,45

INTRODUCTION

8

When medications are administered as a prolong IV infusion, clinical staff require appropriate training and need to regularly monitor their patients throughout the IV infusion.46–48 Indeed, the Medicines and Healthcare Products Regulatory Agency (MHRA) investigated incidents involving infusion pumps in the UK from 2005 to 2010. Their findings were published in a document that highlighted frequent issues related to the use of IV infusion pumps, encouraged the reporting of related adverse incidents, and provided guidance on formalised and validated competence-based training.46

Medication errors that cause patient injury are the most common type of adverse event.49–51 Not all errors lead to adverse events; however, there are some drugs that are at higher risk to cause adverse events when used mistakenly. Drugs that have increased risks of causing significant patient harm when used in error are called ‘high-alert medications’. Since 2007, IV oxytocin has been on the list of high-alert medications released by the Institute for Safe Medical Practices.52 Medication errors related to IV oxytocin usage are mainly dose related.53,54

Carbetocin is a long-acting synthetic analogue of human oxytocin that is indicated for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia. It has a similar onset of action to oxytocin,55–57 but demonstrates a longer half-life.58–60 Carbetocin is given as a single IV injection, which is administered slowly over 1 minute only after delivery of the infant by caesarean section.61 A new room temperature-stable formulation has recently been developed (see Section 3.1), which no longer needs to be kept under refrigerated conditions (2–8°C) but must be stored below 30°C, and is now available in a more convenient vial presentation.61

Compared to oxytocin, carbetocin is equally effective in reducing the risk of PPH or severe PPH, but significantly reduces the need for additional uterotonics and uterine massage,62–65 while significantly increasing the time to additional uterotonics.63 More women who receive carbetocin experience bleeding ≤500 mL compared with oxytocin (81 vs 55%; p=0.05).64 Data from one study also suggest that carbetocin is associated with significantly lower levels of perceived post-operative pain following caesarean delivery compared with oxytocin.66 The adverse event profiles of oxytocin and carbetocin are comparable.62

This monograph discusses current PPH prevention and management strategies, including the benefits of active management, and provides an up-to-date review of all the currently available data on the chemistry, pharmacology, efficacy and safety of carbetocin.

9

Ferring Pharmaceuticals is a research-driven biopharmaceutical company devoted to identifying, developing and marketing innovative products in the field of obstetrics and gynaecology. As a company, Ferring is committed to developing products based on the body’s own terms. Ferring aims to provide the best prevention and treatment to aid in every stage of the reproductive cycle, especially during pregnancy, to ensure a safe and successful process for the mother and her baby.

Pregnancy and childbirth pose significant health risks, even in the developed world, and more so in the developing world. This is reflected by the United Nations’ (UN) initiatives to significantly improve maternal and neonatal health by 2015 via the Millennium Development Goals.67 It has been estimated that 40% of women experience pregnancy-related health problems during or after pregnancy and childbirth, with 15% suffering life-threatening complications.68 Every day, nearly 800 women, on average, die from pregnancy and childbirth-related complications, totalling 289,000 women worldwide in 2013.69 The management of such risks necessitates continued research and development in obstetrics.

Ferring is dedicated to reducing undesirable maternal and neonatal morbidity and mortality during pregnancy and delivery, and to improving the woman’s journey through childbirth. Our obstetric therapies reflect this commitment and range from the management of preterm labour70 to the induction of labour71 and the prevention of PPH.61

Carbetocin is indicated for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia and is given as a single IV injection. It is the first approved, room temperature-stable uterotonic agent available for this condition.61

Carbetocin is also approved for the prevention of uterine atony in women at risk of PPH following vaginal delivery in several countries (including to date Russia, Mexico, Kazakhstan, Cuba, Ecuador, El Salvador and Honduras)72–74 and for the treatment of uterine atony in Mexico.74

FERRING AND OBSTETRICS

10

1.1 DEFINITION OF POSTPARTUM HAEMORRHAGEThe traditional definition of PPH is a bleed of 500 mL or more in vaginal deliveries and in excess of 1000 mL in abdominal deliveries, as quoted by the WHO,10 the American College of Obstetricians and Gynecologists (ACOG),75 and the International Federation of Gynecology and Obstetrics (FIGO).14 Haemorrhage during the first 24 hours after delivery is termed ‘early’ or ‘primary’ PPH, whereas ‘late’ or ‘secondary’ PPH occurs more than 24 hours after, but within 6–12 weeks of delivery.14,75

However, women vary in their tolerance to blood loss, and a healthy woman may be able to tolerate bleeding at these volumes during delivery.76 By contrast, haemodynamically destabilising factors, such as anaemia or dehydration, could reduce the tolerance to blood loss.4 In addition, clinicians usually estimate the volume of blood lost by women via a subjective visual, and thus approximate, estimation that may lead to erroneous evaluations; it has been shown that blood loss is generally underestimated by an average of 100–140 mL.77–79

A study comparing visual estimation with direct measurement of blood loss in women undergoing vaginal delivery reported the incidence of PPH as 5.7 and 27.6%, respectively, which corresponds to an underestimation of the incidence of PPH with visual estimation approaching 90%.78 Similarly, other investigators have shown inaccuracies in the estimation of blood loss following caesarean deliveries, including both under- and over-estimation of blood volume.80–84

Several studies have demonstrated that the higher the measured blood loss, the greater the underestimation by visual assessment.79,82,85 Indeed, there is a tendency towards greater underestimation with a calculated blood loss >1000 mL; for example, one study that included 90 caesarean deliveries with calculated blood loss >1000 mL found that only 16 (18%) of these cases were correctly estimated by clinicians.84 Conversely, blood loss has been shown to be overestimated at low volumes (<150–250 mL) in both vaginal82 and caesarean deliveries.81

Given that the traditional definition of PPH, based on the quantification of blood loss, has several limitations, other alternative classifications have been proposed over the years. For example, PPH has been defined by some investigators as a 10% change in haematocrit between admission and the postpartum period.86 However, the use of haematocrit change is not clinically useful in emergency situations, such as PPH, where acute blood loss is mostly not reflected by an immediate reduction in haematocrit or haemoglobin concentration, and the peak drop may not occur until 2 or 3 days after the bleeding event.87

A definition of PPH based on the need for blood transfusion is also of limited value, as the practice of blood transfusion varies extensively.88 Similarly, PPH definitions based on symptoms of haemodynamic instability (e.g. hypovolemic shock, tachycardia and hypotension) are not useful since they represent only late signs of depleted blood volume and may signal failure of compensatory mechanisms, which can be life-threatening to the mother.88–90 Thus, there is currently no single, satisfactory, definition of primary PPH.

As a result of these difficulties, some guidelines, such as those released by FIGO in 2012, by the Society of Obstetricians and Gynaecologists of Canada (SOGC) in 2009 and by ACOG in 2006, now acknowledge that there is no standard definition of PPH and describe it simply as any blood loss that has the potential to produce haemodynamic instability (Table 1).13,14 In the UK, the 2009 guidelines issued by the Royal College of Obstetricians and Gynaecologists (RCOG) only recommend a full intervention at the higher threshold of 1000 mL of blood loss, unless signs of clinical shock are present (e.g. weakness, sweating or tachycardia).11

CHAPTER I

11

Table 1. Definition of postpartum haemorrhage according to various international and national guidelines

Guideline Definition of PPH

WHO (2012)10 • Blood loss of ≥500 mL occurring within 24 hours after birth

FIGO (2012)14 • Vaginal delivery: >500 mL of blood loss• Caesarean delivery: >1000 mL of blood loss • Any volume of blood loss that has the potential to produce haemodynamic instability

should be considered as PPH

SOGC (2009)13 • For clinical purposes, any blood loss that has the potential to produce haemodynamic instability should be considered as PPH

RCOG (2009)11 • Primary PPH: 500–1000 mL of blood loss• Major PPH: >1000 mL of blood loss, which can be categorised as:

– Moderate: 1000–2000 mL – Severe: >2000 mL

ACOG (2006)75 • No single satisfactory definition• Quote standard definition:

– Vaginal delivery: >500 mL of blood loss – Caesarean delivery: >1000 mL of blood loss

ACOG=American College of Obstetricians and Gynecologists; FIGO=International Federation of Gynecology and Obstetrics; PPH=postpartum haemorrhage; RCOG=Royal College of Obstetricians and Gynaecologists; SOGC=Society of Obstetricians and Gynaecologists of Canada; WHO=World Health Organization

1.2 INCIDENCE OF POSTPARTUM HAEMORRHAGEThe true incidence of PPH is difficult to determine, particularly as many studies and monitoring reports do not use a valid definition or are otherwise lacking.91 Most reports place the incidence of the condition at 1–10% of live births,91–93 with the majority of haemorrhages occurring within 24 hours (primary PPH).21 An analysis of 38 epidemiological surveys between 1997 and 2006 showed an overall PPH incidence of 6.1% (out of a population of over 3,800,000), with severe PPH at 1.9% (out of a population of over 500,000).91 Regional incidence varied from 2.6% in Asia to 10.5% in Africa, whereas Europe and North America both reported an incidence of 6.4%. The elevated PPH rate in Africa may potentially reflect the lack of resources in low-income countries, as well as the lack of skilled or qualified birth attendants.67,94 However, the contribution of data from developing countries to these types of analyses is often lacking; women from Europe comprised 86% of the population covered by this analysis.91

A recent trend for increasing rates of PPH has been observed in several studies conducted in developed countries, with absolute increases in incidence of 1.1–2.6% over periods of approximately 10 years since 2000.9,95,96 This trend has largely been driven by an increase in atonic PPH, but the reasons behind this remain unclear.9,20,95–97

12

1.3 IMPACT OF POSTPARTUM HAEMORRHAGEMaternal mortality has declined by 45% between 1990 and 2013, following the UN Millennium Development Goals to improve maternal health.67 However, 289,000 mothers worldwide still died from pregnancy-related causes in 2013.69 Previous research has suggested that almost half of such deaths occur in the first 24 hours after delivery (Figure 1).98 Pregnancy-related bleeding accounted for 27% of global maternal deaths between 2003 and 2009, with PPH reported as the cause of 19.7% of deaths overall.1

The overwhelming majority of deaths caused by PPH occur in developing countries, with Sub-Saharan Africa and Southern Asia alone accounting for over 80% of global PPH-induced maternal mortality. By contrast, deaths due to PPH are only 0.25% in developed countries. In developing regions, PPH is associated with 19.7% of all maternal deaths from any cause, compared with 8% in developed countries.1

Complications arising from PPH include the requirement for blood transfusion and the resulting risk of infection or adverse reaction,99 the need for surgical interventions such as uterine artery ligation or permanent sterilisation through hysterectomy,3 and delayed milk production.100 Another possible result of severe PPH is deprivation of oxygen, which can seriously damage vital tissues and organs. In the case of Sheehan’s syndrome, the necrotic damage occurs to the pituitary gland (a small gland at the base of the brain) and leads to the underproduction of essential pituitary hormones (hypopituitarism), which can vary in severity, depending on the patient.101 It is one of the most common causes of hypopituitarism in underdeveloped or developing countries; for example, it has an estimated prevalence of 3% in India.102 However, the condition is rare in developed countries.103,104

Sheehan’s syndrome can cause deficiency of one or more of the hormones secreted by the pituitary gland; in particular, the lack of prolactin results in the loss of milk production.105 Failure to breastfeed can also arise from the treatments and trauma associated with labour and delivery, which prolong the separation of the mother and baby and thus lead to the need of feeding the baby with milk products while the mother recovers.100 In addition, women who experienced severe PPH may have long-term psychological problems despite uterine preservation; for example, deciding against or delaying having another baby due to the fear of a recurrence of PPH, intense anxiety throughout subsequent pregnancy, and a potential risk of developing depression during pregnancy.106

13

1.4 AETIOLOGY OF POSTPARTUM HAEMORRHAGEThere are four principal causes of primary PPH, commonly referred to as the ‘four Ts’:11,14

1. Tone: uterine atony, accounting for approximately 80% of PPH cases,20,96 or distended bladder

2. Trauma: uterine, cervical or vaginal injury

3. Tissue: retained placenta or clots

4. Thrombin: pre-existing or acquired coagulopathy

Several risk factors may increase the likelihood of a woman to develop PPH: some are associated with the four Ts (Table 2),11 while others relate to fertility treatment,107 hypertension,9,107 amnionitis,9,86 and Asian or Hispanic ethnicity.86 However, although risk factors may increase the likelihood of haemorrhage in a given woman, the majority of PPH cases occur with no known associated risk factors.10,75

Secondary PPH, which occurs from 24 hours after delivery up to 6 weeks postpartum,14,75

may be associated with different risk factors and the most frequent are subinvolution of the placental bed, infection, inflammation and retained placental product.108

50

45

40

35

30

25

20

15

10

5

00–1 2–7 8–14

Days after delivery

15–21

United States

Developing countries

22–30 31–42

Mat

erna

l dea

ths

(%)

Figure 1. The majority of maternal deaths in the United States of America and in developing countries occur in the first week after birth of the baby98

14

Table 2. Risk factors associated with the four principal causes of primary postpartum haemorrhage

Cause Risk factor

Tone Known placenta praeviaMultiple pregnancy Previous PPH Prolonged labour (>12 hours) Prolonged third stage of labourProlonged treatment with oxytocin Obesity (BMI >35 kg/m2) Age (>35 years, not multiparous) Fetal macrasomia (an abnormally large baby [≥4.5 kg])Fibroids Induction of labour General anaesthesia Gestation <37 weeks or >42 weeks

Trauma Emergency caesarean section Elective caesarean section Previous caesarean section Tears/episiotomyOperative vaginal delivery Fetal macrasomia (≥4.5 kg)Perineal suture Genital tract lacerationPerineal tears

Tissue Retained placenta Placenta accreta

Thrombin Placental abruptionPre-eclampsia/gestational hypertensionAnaemia (<10 g/dL)

BMI=body mass index; PPH=postpartum haemorrhage

1.4.1 Uterine atonyUterine atony is the loss of tone in the muscles of the uterus, which results in its failure to contract adequately after delivery. As the primary mechanism of immediate haemostasis following delivery is uterine myometrial contraction, resulting in the occlusion of blood vessels that pass between uterine muscle cells,14 the absence of uterine tone impairs the physiological control of postpartum bleeding.109 Fatal PPH can result from uterine atony despite normal coagulation. Conversely, fatal haemorrhage from the placental implantation site is unlikely in the presence of vigorous uterine contraction, regardless of coagulation status.14 A number of factors can affect the ability of the uterus to contract, including physical (e.g. fetal macrosomia [abnormally large baby] and multiple pregnancy) or pharmacological (e.g. general anaesthesia) elements (Table 2).8,9,86,107,110

The development of PPH may be correlated with the length of the third stage of labour,6,86,111 which begins when the baby is delivered, and ends with the delivery of the placenta and associated membranes. The placenta is usually delivered rapidly, within 5 minutes in 50% of cases and within 15 minutes in 90% of cases,111 and a retained placenta represents an important cause of PPH.112 A prolonged third stage of labour has been correlated with PPH in a prospective, observational study of 6588 vaginal deliveries. The median duration of the third stage of labour was not significantly different in women with or without PPH (9 vs 7 minutes), and was comparable to that identified in previous studies.113

15

However, women with a third stage of labour longer than 10 minutes (odds ratio [OR] 2.1 [95% confidence interval [CI]: 1.6, 2.6]; p<0.001), 20 minutes (OR 4.3 [95% CI: 3.3, 5.5]; p<0.001) and 30 minutes (OR 6.2 [95% CI: 4.6, 8.2]; p<0.001) were progressively more likely to experience PPH. The authors determined that a delay of 18 minutes or more before placental delivery was the most predictive threshold for PPH, with a sensitivity of 31% and a specificity of 90%.6

1.4.2 Uterine, cervical or vaginal traumaCaesarean section is itself a form of uterine trauma and PPH occurs more frequently in caesarean than in vaginal deliveries.9,93 Caesarean section rates are now approximately 26–33% of births in a number of developed countries,95,114–116 in contrast to the 10–15% upper limit suggested by the WHO.117

The possibility of lacerations should be considered when bleeding persists in the presence of adequate uterine tone.75 The reproductive tract lacks the vigorous contractile activity of the uterus, so bleeding from lacerated or incised blood vessels cannot be rapidly controlled in the same way. Lower genital tract lacerations secondary to obstetric trauma occur more commonly with forceps delivery or vacuum extraction than with spontaneous vaginal delivery. Other risk factors include macrosomia and precipitous labour/delivery.118

1.4.3 Retained placental tissueA retained placenta is one that has failed to be delivered by 30 minutes after the birth of the baby.119 Near term, 600–700 mL/minute of blood flows through the intervillous spaces that make up the maternal blood compartment of the placenta.120 When the placenta separates from the uterine wall, the arteries and veins that carry this blood are inevitably severed, leading to blood loss. Uterine myometrial contraction is the key mechanism for achieving rapid haemostasis following this bleeding.121 When all or part of the placenta is retained, this is likely to impair uterine contraction and involution, thus inhibiting this haemostatic process.122

Retained placental tissue and associated membranes are responsible for 5–10% of cases of PPH.112 Depending on the cause, retained placenta can take the form of placenta adherens (failure of myometrial contraction to separate the placenta), trapped placenta (closed cervix prevents placental expulsion) or partial placenta accreta (when a small area fails to detach).123 Placenta accreta is a rare condition whereby the placenta invades the uterine myometrial wall itself, preventing its normal separation from the uterus during the third stage of labour.109,124 It is associated with massive PPH and a high mortality rate,11 with one study by O’Brien et al. reporting an incidence of maternal death as high as 7%.125

1.4.4 Pre-existing or acquired coagulopathyCoagulopathies are conditions that affect the ability of the blood to clot, leaving patients more prone to extended bleeding. Pre-existing coagulopathies can also be a rare cause of PPH. Examples of coagulopathies are haemophilia and von Willebrand’s diseases, which are inherited genetic conditions altering the ability of the blood to clot; thus, affected patients may experience extended or excessive bleeding.7,126 Where there is no existing diagnosis, menorrhagia may be an early sign of a pre-existing coagulation disorder7,127 that can prompt further investigation. Indeed, coagulation deficiency tests that can be run at the bedside (e.g. to measure fibrinogen levels) have been developed.128,129 Women with known bleeding disorders should have their clotting factors monitored in the lead-up to delivery. Bleeding due to a coagulation deficiency requires prothrombotic treatment, such as clotting factor replacement or tranexamic acid.126

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1.5 DIAGNOSIS OF POSTPARTUM HAEMORRHAGEOne of the most common problems in the management of obstetric haemorrhage is a delay in diagnosis and treatment.130 Therefore, to improve outcomes and avoid preventable death, early recognition of women who might be prone to PPH is a key element76 and to this end, studies have identified several risk factors (see Section 1.4 and Table 2). However, many cases of PPH occur without any identifiable predisposing characteristic.10,75

PPH is defined by blood loss volume, and prompt detection and appropriate care are key to decreasing the risk of developing PPH (Table 1).77,88 Therefore, an accurate estimation of blood loss is a crucial element of postpartum care.88 However, clinicians usually evaluate blood loss volume by a subjective visual estimation at delivery, often resulting in under estimation by up to 50%.77,131

There are several quantitative and more accurate methods to estimate blood loss (e.g. photospectrometry, radioisotope dilution and gravimetric methods),131,132 but they generally require special equipment and are expensive and time-consuming. These make them impractical in the setting of a delivery suite and unsuitable for life-threatening situations.131,133 Hence, the visual real-time approximate estimations are more commonly used.131

The accuracy of the visual evaluation of blood loss volume can be improved by different means: training healthcare personnel to carefully evaluate the different types of blood spillage (e.g. on the bed, on the floor or in a pan),85 repeating the visual estimation at multiple different time points,131 and counting saturated swabs whose capacities at saturation has been previously evaluated.90

The use of blood collection drapes can further increase visual estimation accuracy. They consist of a funnel and collecting pouch attached to a plastic sheet that is placed under the woman’s buttocks immediately after delivery.77 Collection drapes are also available in calibrated versions that include volume markings and can further ameliorate the level of precision.133

The diagnosis of PPH solely based on the volume of blood lost may not truly reflect the haemodynamic status of a woman owing to variable individual responses to haemorrhage and thus lead to inconsistent management of the condition. Therefore, the classification of PPH should take into consideration both the volume lost and clinical consequences resulting from the blood loss, which should be assessed with parameters that are easily measurable and reproducible.134 Consequently, it has been suggested that the traditional WHO definition of PPH as a loss of blood >500 mL should be treated as an ‘alert’ line for increased monitoring, unless other signs of clinical shock are present.11,134,135

Haemodynamic compromise and clinical shock can manifest as large changes in individual vital signs, such as pulse rate, systolic blood pressure, respiratory rate and temperature. However, the physiological changes associated with pregnancy means that changes normally associated with hypovolaemic shock may not be readily apparent until a significant volume of blood is lost. For example, the increased circulating blood volume during pregnancy will mask any decrease in blood pressure, and a significant drop might only be observed when a large volume of blood (>15%) has already been lost.76,88 Therefore, several vital signs should be evaluated and small changes in each vital sign should be considered together to provide advanced warning of haemodynamic compromise in pregnant women and enable timely intervention.136

17

KEY POINTS PPH is responsible for approximately one-fifth of maternal

mortality worldwide, accounting for 19.7% of maternal deaths in developing nations and 8% in developed countries1

Most maternal deaths occur in the early postpartum period98

Uterine atony is the principal cause of PPH20,96

PPH often occurs without any apparent risk factors10,75

Volume of blood loss is widely underestimated due to the use of visual subjective blood estimation78,79

18

2.1 PREVENTION OF POSTPARTUM HAEMORRHAGE

As most PPH is due to uterine atony following delivery of the baby,20,21,96 appropriate management of the third stage of labour is critical.137 The physiological median duration of this stage of labour is approximately 6 minutes, with the risk of bleeding increasing markedly after 30 minutes.138 Uterine myometrial contraction is the primary mechanism by which excessive bleeding is prevented during normal labour, with the placental implantation site being the most common site of bleeding after delivery. Failure of adequate contraction, defined as uterine atony, can therefore result in PPH.139

2.1.1 Guidelines on the management of the third stage of labour

Management of the third stage of labour to speed up delivery of the placenta and prevent PPH can be either active or expectant. Expectant management (also known as conservative or physiological management) involves waiting for signs that the placenta is separating from the uterine wall and allowing it to deliver spontaneously or aided by gravity or nipple stimulation.10

By contrast, active management of the third stage of labour has traditionally involved a number of key interventions, including:10

1. The administration of a prophylactic uterotonic after the delivery of a baby

2. Early cord clamping and cutting (note that there is no consensus amongst the major international and national guidelines regarding the precise timing of cord clamping)10,11,13,14,23,140

3. The controlled traction of the umbilical cord

4. Uterine massage after delivery of the placenta

Several key national and international guidelines have provided recommendations on the use of each of these components for the active management of PPH, and were compared in a recent review. Generally, there is widespread agreement between guidelines that active management of the third stage of labour should be preferred over expectant management, and that IV oxytocin should be the first-choice medication for prevention of PPH, while there is no unequivocal and consistent recommendation on second and later lines of uterotonic agent to prevent PPH (Table 3).23 However, the SOGC guideline recommends carbetocin over continuous IV infusion of oxytocin as first-line therapy for PPH prevention in elective caesarean deliveries.13 Moreover, the National Center for Health Technology Excellence in Mexico advises that carbetocin can be used instead of continuous infusion of oxytocin for elective caesarean section,12 and the guideline issued by the Queensland Maternity and Neonatal Clinical Guidelines Program in Australia highlights that substitution of oxytocin infusion with carbetocin can be considered in elective caesarean delivery.44 The Polish Society of Gynaecologists and the Ministry of Health of the Russian Federation are very positive towards carbetocin and evaluate it as an effective therapeutic option in caesarean section.141,142 The Polish Society of Gynaecologists favours also the use of carbetocin in individual cases of uterine atony or subatony after vaginal delivery.141

CHAPTER II

19

Both the Philippine Obstetrical and Gynecological Society, and the Chinese Society of Obstetrics and Gynecology recommend carbetocin as an alternative uterotonic; however, none of these two guidelines specify the mode of delivery (elective or clinically-indicated caesarean section, or vaginal birth).15,16 Carbetocin is recommended by the Danish Society of Obstetrics and Gynecology for PPH prevention as an alternative to oxytocin in high risk women (twins, multipara, previous PPH and coagulation disorders) for both caesarean section and vaginal delivery.143

The guidelines issued by WHO, FIGO, RCOG and SOGC broadly agree on the need to delay cord clamping to a varying extent. Their recommendations on controlled cord traction (CCT) (see Section 2.1.4) are more varied, and stress the importance of skilled healthcare professionals performing this procedure.10,11,13,14

Table 3. International and country recommendations on prevention of postpartum haemorrhage

Guidelines Uterotonics Cord clamping Controlled cord traction

Uterine massage

WHO (2012)10 • Oxytocin (10 IU, IV/IM) is the recommended uterotonic drug for the prevention of PPH

• Oxytocin (IV or IM) is the recommended uterotonic drug for the prevention of PPH in caesarean section

• In settings where oxytocin is unavailable, the use of other injectable uterotonics (if appropriate, ergometrine/methylergometrine or the fixed drug combination of oxytocin and ergometrine) or oral misoprostol (600 mcg) is recommended

• In settings where skilled birth attendants are not present and oxytocin is unavailable, the administration of misoprostol (600 mcg PO) by community health care workers and lay health workers is recommended for the prevention of PPH

• Late cord clamping (performed approximately 1 to 3 minutes after birth) is recommended for all births while initiating simultaneous essential newborn care

• Early cord clamping (<1 minute after birth) is not recommended unless the neonate is asphyxiated and needs to be moved immediately for resuscitation

• In settings where skilled birth attendants are available, CCT is recommended for vaginal births if the care provider and the parturient woman regard a small reduction in blood loss and a small reduction in the duration of the third stage of labour as important

• CCT is the recommended method for removal of the placenta in caesarean section

• In settings where skilled birth attendants are unavailable, CCT is not recommended

• Sustained uterine massage is not recommended as an intervention to prevent PPH in women who have received prophylactic oxytocin

FIGO (2012)14 • Oxytocin (10 IU IM) is preferred over other uterotonic drugs because it is effective 2–3 minutes after injection, has minimal adverse effects, and can be used in all women

• If oxytocin is not available, other uterotonics can be used, such as:– Ergometrine or

methylergometrine 0.2 mg IM– Syntometrine (a combination of

oxytocin 5 IU and ergometrine 0.5 mg per ampoule IM)

– Misoprostol 600 mcg orally

• If the newborn is healthy, clamp the cord close to the perineum once cord pulsations stop or after approximately 2 minutes

• Immediate cord clamping may be necessary if the newborn requires resuscitation

• CCT only when a skilled attendant is present at the birth

• CCT is not recommended in the absence of uterotonic drugs or prior to signs of separation of the placenta because this can cause partial placental separation, a ruptured cord, excessive bleeding, and/or uterine inversion

• Uterine massage after delivery of the placenta, as appropriate

20

Table 3. continued


Uterine massage

SOGC (2009)13 • Oxytocin (10 IU), administered IM, is the preferred medication and route for the prevention of PPH in low-risk vaginal deliveries– IV infusion of oxytocin (20 to

40 IU in 1000 mL, 150 mL/hour) is an acceptable alternative

• An IV bolus of oxytocin, 5 to 10 IU (given over 1 to 2 minutes), can be used for PPH prevention after vaginal birth but is not recommended for elective caesarean section

• Carbetocin, 100 mcg given as an IV bolus over 1 minute, should be used instead of continuous oxytocin infusion in elective caesarean section for the prevention of PPH and to decrease the need for therapeutic uterotonics

• For women delivering vaginally with 1 risk factor for PPH, carbetocin 100 mcg IM decreases the need for uterine massage to prevent PPH when compared with continuous infusion of oxytocin

• Ergonovine can be used for prevention of PPH but may be considered second choice to oxytocin owing to the greater risk of maternal adverse effects and the need for manual removal of a retained placenta– Ergonovine is contraindicated

in patients with hypertension• Ergonovine, 0.2 mg IM, and

misoprostol, 600 to 800 mcg given by the oral, sublingual, or rectal route, may be offered as alternatives in vaginal deliveries when oxytocin is not available

• Whenever possible, delaying cord clamping by at least 60 seconds is preferred to clamping earlier in premature newborns (<37 weeks’ gestation) since there is less intraventricular haemorrhage and less need for transfusion in those with late clamping

• No specific guidance


21

Table 3. continued


Uterine massage

CENETEC(Mexico) (2008)12

• It is recommended to administer IM oxytocin 10 IU in low-risk vaginal deliveries after the birth of the anterior shoulder– It is recommended to

administer IV infusion of oxytocin (20–40 IU diluted in 1000 mL, 125 mL/hour). Maximum 40 mIU per minute

• A bolus of oxytocin 5–10 IU can be used for prevention after vaginal delivery but not recommended in elective caesarean delivery

• Ergonovine may be used for prevention of PPH but should be considered as second choice due to the increased risk of adverse effects to the mother and the need for manual removal of retained placenta – It is not recommended to use

ergonovine or syntometrine in patients with hypertension

• It is recommended to administer ergonovine 0.2 mg IM or single IV dose after the birth of the anterior shoulder to prevent PPH

• If oxytocin or ergonovine are unavailable, it is recommended to administer oral misoprostol (prostaglandin E1 analogue) 600 mcg (3 tablets)

• Carbetocin 100 mcg IV bolus administered over 1 minute can be used instead of continuous infusion of oxytocin at elective caesarean section for preventing PPH and to reduce the need for uterotonics

• For women delivering vaginally with a risk factor for obstetric haemorrhage, carbetocin 100 mg IM reduces the need for uterine massage to prevent bleeding when compared with oxytocin infusion

• Clamping and cutting during the first minute of the umbilical cord (recommended as part of the active management of the third stage of labour)

• There are no randomised controlled trials to support the use of fundal pressure instead of CCT as part of the active management of the third stage of labour. Therefore, CCT should remain the method of extraction of the placenta in the active management of labour


22

Table 3. continued


Uterine massage

Polish Society of Gynaecologists (2013)141

• Carbetocin is an effective therapeutic option in the prevention and treatment of PPH after C-section and their negative effects

• According to the team of experts, the application of carbetocin should be also considered in individual cases of atony or subatony of the uterus after vaginal delivery

• In case of atony symptoms after vaginal delivery, the administration of carbetocin should not be considered as a professional error, despite the lack of drug registration for such use (off label), as a procedure saving health and life

• Carbetocin should be found in each delivery room and operating theatre




Queensland Maternity and Neonatal Clinical Guidelines Program (Australia) (2012)44

• Oxytocin 10 IU IM is the prophylactic uterotonic drug of choice

• In elective caesarean section consider substituting oxytocin infusion with carbetocin IV 100 mcg in 1 mL, given slowly over 1 minute after birth of the baby– Carbetocin is for use in

elective caesarean section and is currently not indicated in emergency caesarean section or after vaginal birth

• In active management the ability to minimise hypertensive effects and interference of placental transfusion by:– Omitting the ergot

component of the prophylactic uterotonic

– Delaying cord clamping (for 2–3 minutes)

• Commence CCT with a strong uterine contraction and after signs of placental separation

• Massage uterine fundus after birth of the placenta, as appropriate

23

Table 3. continued


Uterine massage

RCOG (2009)11 • For women without risk factors for PPH delivering vaginally, oxytocin (5 IU or 10 IU by IM injection) is the agent of choice for prophylaxis in the third stage of labour

• For women delivering by caesarean section, oxytocin (5 IU by slow IV injection) should be used to encourage contraction of the uterus and to decrease blood loss

• Syntometrine® (Alliance) may be used in the absence of hypertension (for instance, antenatal low haemoglobin) as it reduces the risk of minor PPH (500–1000 mL) but increases vomiting

• Misoprostol is not as effective as oxytocin but it may be used when the latter is not available, such as the home-birth setting

• The RCOG recommends that the time at which the cord is clamped should be recorded. Early cord clamping is defined as immediately or within the first 30 seconds. The cord should not be clamped earlier than is necessary, based on clinical assessment of the situation

• Evidence suggests that delayed cord clamping (more than 30 seconds) may benefit the neonate in reducing anaemia, and particularly the preterm neonate by allowing time for transfusion of placental blood to the newborn infant, which can provide an additional 30% blood volume

• Early clamping may be required if there is PPH, placenta praevia or vasa praevia, if there is a tight nuchal cord or if the baby is asphyxiated and requires immediate resuscitation



ACOG (2006)75 • In an effort to prevent uterine atony and associated bleeding, it is routine to administer oxytocin soon after delivery




ACOG=American College of Obstetricians and Gynecologists; CCT=controlled cord traction; CENETEC=National Center for Health Technology Excellence (Mexico); FIGO=International Federation of Gynecology and Obstetrics; IM=intramuscular; IV=intravenous; PO=oral administration; PPH=postpartum haemorrhage; RCOG=Royal College of Obstetricians and Gynaecologists; SOGC=Society of Obstetricians and Gynaecologists of Canada; WHO=World Health Organization

24

A Cochrane analysis conducted in 2011 compared active management of the third stage of labour with expectant management, and confirmed that active intervention significantly reduced the risk of severe primary PPH, defined as blood loss ≥1000 mL at the time of birth (data from three studies [4636 women]; risk ratio [RR] 0.34 [95% CI: 0.14, 0.87]; p=0.024) and mean haemoglobin levels <9 g/dL (data from two studies [1572 women]; RR 0.50 [95% CI: 0.30, 0.83]; p=0.0076) (Figure 2).5 Active management also significantly reduced the mean maternal blood loss volume and the need for additional uterotonics compared with expectant management.5 However, potential risks associated with active management were also identified, including an increased rate of hypertension, higher risk of mothers returning to hospital due to bleeding and a potential decrease in average newborn blood volume, and hence newborn birth weight.5

2.1.2 Uterotonic agentsThe administration of a uterotonic agent immediately after delivery of the baby is one of the most important interventions in the prevention of PPH.10 Uterotonic agents currently in use include the endogenous hormone oxytocin, its synthetic long-acting analogue carbetocin, ergot alkaloids, syntometrine (the combination of ergometrine and oxytocin), and injectable prostaglandins.23

Figure 2. A Cochrane systematic review showed that active management of the third stage of labour significantly reduces the rate of severe primary postpartum haemorrhage versus expectant management5

Study or subgroup

Active management

n/N

Expectant management

n/N

Risk ratio M-H, random,

95% CI Weight

Risk ratio M-H, random,

95% CI

Begley 1990 1/705 11/724 15.3% 0.09[ 0.01, 0.72 ]

Prendiville1988 7/846 26/849 40.2% 0.27[ 0.12, 0.62 ]

Rogers 1998 13/748 20/764 44.5% 0.66[ 0.33, 1.32 ]

Total (95% CI) 21/2299 57/2337 100.0% 0.34[ 0.14, 0.87 ]

Test for overall effect: p=0.024

0.01 0.1 1 10 100

Favoursactive

Favoursexpectant

CI=confidence interval; M-H=Mantel-Haenszel; n=number of women; N=total number of women

25

2.1.2.1 OxytocinOxytocin is the most commonly used uterotonic agent,93,144 and is recommended by the majority of clinical guidelines as the first-line uterotonic for PPH prophylaxis for both caesarean and vaginal delivery.13,23

Despite the acknowledged therapeutic role of oxytocic agents in the third stage of labour, the true physiological role of oxytocin during this period remains unclear.109 Oxytocin acts on receptors in the uterine smooth muscle to stimulate contraction of the myometrium145 and the production of prostaglandins by the decidua.146 Prostaglandins themselves are key modulators of myometrial contraction, suggesting that oxytocin may stimulate uterine contraction by direct interaction with the myometrium and indirectly by inducing the formation of prostaglandins on other tissues.145

Oxytocin has a rapid onset of action (causing an almost immediate effect after IV administration and after approximately 2 minutes following IM injection)56,57 and a plasma half-life ranging 3–20 minutes.33 In women, the half-life of a single IV injection of 2 or 5 IU oxytocin is approximately 3–5 minutes,59,60 while one study in men has demonstrated an elimination half-life of 20 minutes following an IV injection of 1 IU oxytocin administered over 1 minute.147 The label for oxytocin in some European countries (UK, France, Italy, Spain and Germany) recommends different routes of administration, which can vary from IM to IV injection, and typically use a dose ranging 5–10 IU.31–35 With regard to IV methods, the UK label recommends diluting 5 IU of oxytocin in physiological electrolyte solution and administering as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes.33 Similarly, the French label advocates diluting 5 IU of the drug in 500 mL of isotonic glucose solution for continuous IV infusion, or preferably through an infusion pump with variable speed for more than 5 minutes.35 These contrast with the Spanish label, which recommends dissolving 10–40 IU of oxytocin in 1000 mL of non-moisturising solvent and infusing at a rate necessary to control uterine atony,31 and with the Italian and German labels, which recommend 5 IU slow IV infusion and 5–6 IU IV infusion (no rate specified), respectively.32,34

In agreement with the variations observed in the label, several administration modalities and dosages of oxytocin are used in clinical practice and recommended by some major international and national guidelines (Table 4). Prolonged IV infusion of 1–8 hours has been investigated in clinical studies,36–42 which may be preceded either by a 5 IU IV bolus or a 40 IU IV infusion over 30 minutes.40 Similarly, guidelines issued by SOGC and the National Center for Health Technology Excellence in Mexico recommend a prolonged IV infusion as an alternative to IM injection for PPH prevention.12,13 Some guidelines also recommend an IM injection of 10 IU.10,11,13,14,44 The use of IV bolus injections has been reported,43 but this is associated with rapid hypotensive side effects and rebound tachycardia that can lead to myocardial ischaemia in women with pre-existing cardiac conditions.33,148

A recent Cochrane review compared the use of oxytocin with placebo for the prevention of PPH. The prophylactic administration of oxytocin reduced the incidence of PPH (relative risk [RR] 0.53 [95% CI: 0.38, 0.74]; p<0.001) and the need for further uterotonics (RR 0.56 [95% CI: 0.36, 0.87]; p=0.01) compared with placebo.29 Furthermore, in comparison with ergot alkaloids or injectable prostaglandins, oxytocin had similar efficacy but was associated with significantly fewer side effects, including nausea and vomiting.

26

Table 4. Oxytocin has been used with a wide range of administration methods, dosing and timing

Source Mode of administration Dose and time

WHO (2012)10 IV/IM bolus 10 IU

FIGO (2012)14 IM bolusIV slow bolus

10 IU5 IU

RCOG (2009)11 IM bolus 5 or 10 IU

SOGC (2009)13 IM bolusIV infusion

10 IU20–40 IU in 1000 mL, 150 mL/ hour

Sarna (1997)36 IV bolus/rapid infusion 5, 10, 15 or 20 IU at 1 IU/minute

Munn (2001)37 IV infusion 80 IU over 30 minutes + 20 IU over 8 hours 10 IU over 30 minutes + 20 IU over 8 hours

Davies (2005)38 IV bolusIV infusion

10 IU 10 IU over 4 hours

Murphy (2009)39 IV bolusIV bolus + infusion

5 IU 5 IU bolus + 30 IU over 4 hours

King (2010)40 IV bolus + infusionIV infusion

5 IU bolus + 40 IU over 30 minutes + 20 IU over 8 hours 40 IU over 30 minutes + 20 IU over 8 hours

Güngördük (2010)41 IV bolusIV bolus + infusion

5 IU bolus 5 IU bolus + 30 IU over 4 hours

Tita (2012)42IV infusionIV infusionIV infusion

80 IU over 1 hour 40 IU over 1 hour10 IU over 1 hour

FIGO= International Federation of Gynecology and Obstetrics; IM=intramuscular; IV=intravenous; RCOG=Royal College of Obstetricians and Gynaecologists; SOGC=Society of Obstetricians and Gynaecologists of Canada; WHO=World Health Organization

2.1.2.2 CarbetocinCarbetocin is a synthetic analogue of oxytocin and is the only approved room temperature-stable uterotonic for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia.61 Like oxytocin, carbetocin binds at the oxytocin receptor and induces uterine myometrial contraction through a similar molecular mechanism (see Section 3.3).149,150

Carbetocin has a similar onset of action to oxytocin when administered by IV (1.2 minutes versus an almost immediate effect)55,57 or IM (2.3 vs 2.5 minutes),55,56 but demonstrates a half-life that is eight-times longer (40 vs 3–5 minutes).58–60 The duration of action with a single IV injection of carbetocin is 60 minutes;55 however, when given as an IM injection, the effects last for 119 minutes, which is longer than for IM oxytocin (approximately 30 minutes).55,56

27

Carbetocin is indicated for the prevention of uterine atony in women undergoing caesarean section61 and is recommended over continuous IV infusion of oxytocin as first-line option for elective caesarean delivery by SOGC.13 The Danish Society of Obstetrics and Gynecology recommend carbetocin for PPH prevention as an alternative to oxytocin in high risk women (twins, multipara, previous PPH and coagulation disorders) for both caesarean section and vaginal delivery.143 Furthermore, the National Center for Health Technology Excellence in Mexico indicates that an IV injection of carbetocin (100 mg in 1 mL given over 1 minute) can be used instead of continuous infusion of oxytocin for elective caesarean section.12

Similarly, the guidelines issued by the Queensland Maternity and Neonatal Clinical Guidelines Program in Australia considers carbetocin as an alternative to oxytocin infusion in elective caesarean section,44 and those issued by the Polish Society of Gynaecologists and the Ministry of Health of the Russian Federation recommend carbetocin for caesarean sections, without providing specific guidance on whether or not it should be first-line option.141,142 Besides caesarean deliveries, the Polish Society of Gynaecologists also propose the use of carbetocin after vaginal delivery when uterine atony is evident, and recommends that carbetocin be available in “each delivery room and operating theatre.”141 In addition, the Philippine Obstetrical and Gynecological Society, and the Chinese Society of Obstetrics and Gynecology recommend carbetocin as an alternative uterotonic, without specifying the mode of delivery.15,16 Carbetocin will be discussed in detail in Chapters 3 and 4 of this monograph.

2.1.2.3 Ergot alkaloidsErgot alkaloids, such as ergometrine (also known as ergonovine) and methylergometrine (a synthetic analogue of ergometrine),151 increase the amplitude and frequency of uterine contractions and tone, thus impeding uterine blood flow. Haemostasis is achieved through contractions of the uterine wall around bleeding vessels at the placental site. Ergometrine also stimulates arterial vasoconstriction by stimulation of the α-adrenergic and serotonin receptors.152

When administered IV, ergot alkaloids are associated with a significantly decreased risk of PPH (RR 0.38 [95% CI: 0.21, 0.69]; p=0.0017) versus placebo.26 By contrast, data from five randomised clinical trials indicate that oxytocin is more effective than ergot alkaloids in preventing PPH (RR 0.76 [95% CI: 0.61, 0.94]; p=0.014).29 Moreover, ergot alkaloids are associated with significantly increased nausea (RR 0.18 [95% CI: 0.06, 0.53]; p=0.0017) and vomiting (RR 0.07 [95% CI: 0.02, 0.25]; p<0.001), compared with oxytocin.29

Ergometrine can also be given alongside oxytocin, in a combination known as syntometrine. However, there is no advantage to syntometrine compared with ergometrine alone in PPH prevention.29 Although syntometrine was significantly more effective than oxytocin at preventing PPH ≥500 mL (OR 0.82 [95% CI: 0.71, 0.95]; p=0.007), it was also associated with a significantly greater risk of elevated blood pressure (OR 2.40 [95% CI: 1.58, 3.64]; p=0.00004), nausea (OR 4.07 [95% CI: 3.43, 4.84]; p<0.00001) and vomiting (OR 4.92 [95% CI: 4.03, 6.00]; p<0.00001).153

28

2.1.2.4 ProstaglandinsProstaglandins are potent stimulators of myometrial contractility, acting via cyclic AMP-mediated calcium release.109 In the myometrium, the two major stimulating prostaglandins are prostaglandin F2α (PGF2α) and prostaglandin E (PGE).154 Within the PGE class, PGE1 has a greater effect on uterine contractility than PGE2.155

Misoprostol is a synthetic analogue of PGE1 that was developed for the treatment of non-steroidal anti-inflammatory drug-induced peptic ulcers.156 Misoprostol has been used off-label for the prevention of PPH,157 especially in low income countries and in a home birth setting where injectable uterotonics may not be available or cannot be used safely as births are often not attended by skilled healthcare professionals.158 A Cochrane review conducted in 2012 showed that, as compared with placebo, sublingual misoprostol (one trial with 661 women; RR 0.66 [95% CI: 0.45, 0.98]; p=0.037) was effective in reducing severe PPH, while oral misoprostol reduced the need for blood transfusion (four trials with 3519 women; RR 0.31 [95% CI: 0.10, 0.94]; p=0.039). However, compared with conventional injectable uterotonics (oxytocin in most of the trials), oral misoprostol was associated with a higher risk of severe PPH (RR 1.33 [95% CI: 1.16, 1.52]) and use of additional uterotonics. Moreover, oral misoprostol was associated with a greater incidence of nausea, vomiting, diarrhoea, shivering and pyrexia (greater than 38°C), as compared with both placebo and other uterotonics. The authors concluded that misoprostol was not preferable to conventional injectable uterotonics and that further research was needed to determine the lowest effective dose and best route of administration. Nevertheless, they also highlight that misoprostol can be an option in areas with low access to facilities and a paucity of skilled healthcare providers.27

In spite of the above-mentioned limitations, misoprostol is recommended in some guidelines, although only as an alternative option to be used in the absence of first-line oxytocin or other injectable uterotonics (ergometrine and syntometrine), or when these cannot be used (Table 3).10,11,14 In line with this, a recent review concluded that, in developed countries, oxytocin should remain the treatment of choice for PPH prophylaxis due to the lower efficacy and less favourable side effect profile associated with misoprostol.159

The PGE2 analogue sulprostone has been used to prevent PPH,27,160 but data on its efficacy are lacking. One trial suggested that sulprostone may be as effective as oxytocin at reducing postpartum blood loss, although this was in the context of expectant management of the third stage of labour.160 However, a second trial was stopped prematurely after the manufacturer issued a warning about serious cardiovascular side effects following IM sulprostone use.27 Further, a Cochrane review of the use of prostaglandins (including carboprost tromethamine) as part of the management of the third stage of labour observed that conventional injectable uterotonics (IV or IM oxytocin, ergometrine or their combination) were preferred over IM prostaglandins to prevent PPH, especially in women who were at low risk for PPH, and were associated with a significantly higher incidence of adverse events.27 Dinoprostone, in the form of a vaginal insert, has also been compared with IV oxytocin in one trial, which found a comparable mean blood loss and need for additional uterotonics between the two groups. However, dinoprostone was associated with more side effects than oxytocin, and the PGE2 medication was not considered cost-effective for PPH prevention.30

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2.1.3 Cord clampingClamping of the umbilical cord is an essential part of the management of the third stage of labour.161 It consists of placing one clamp close to the infant’s navel and a second one further along the umbilical cord, and subsequent cutting of the cord between the clamps.161 The ideal timing for umbilical cord clamping has yet to be established, but can range from 30 seconds to 3 minutes after birth.10,140,161 Early cord clamping (within 1 minute of delivery) results in a decrease of 20 to 40 mL/kg of blood in term newborns; however, a delay in clamping causes increased neonatal total blood volume, potentially leading to neonatal complications, such as respiratory distress, jaundice and polycythaemia.13 As such, the timing of cord clamping may vary according to clinical policy and practice.

A recent Cochrane review of 15 trials involving 3911 women undergoing either early or late cord clamping observed no difference between the two groups regarding the proportion of women presenting with PPH or severe PPH. However, infants who underwent early cord clamping had significantly lower haemoglobin concentrations at 24–48 hours (mean difference –1.49 g/dL [95% CI: –1.78, –1.21]; p<0.00001) and were significantly more likely to be iron deficient at 3–6 months (RR 2.65 [95% CI: 1.04, 6.73]; p=0.041) than those whose cords were clamped late. Delayed cord clamping was also associated with a higher birth weight (mean difference 101 g [95% CI: 45, 157]; p=0.00044), whereas early clamping appeared to reduce the need for phototherapy for jaundice (RR 0.62 [95% CI: 0.41, 0.96]; p=0.032).161 In line with these findings, many guidelines now recommend delayed cord clamping in order to reduce neonatal anaemia, unless the infant is asphyxiated or requires resuscitation.10,11,14

2.1.4 Controlled cord tractionCCT involves pulling downward on the umbilical cord very gently once the uterus has contracted, while simultaneously applying pressure on the uterus by pushing on the abdomen just above the pubic bone to aid in the separation of the placenta from the uterine wall and its subsequent delivery.14

As part of an active management protocol, CCT has been shown to reduce the incidence of PPH and retained placenta, as well as the need for additional uterotonics.162 However, recent trials have suggested that the contribution of the CCT component to reduced blood loss and PPH may not be significant, particularly in high-resource settings.163,164 A large randomised, controlled, trial enrolling over 10,000 women across eight different countries showed that withholding CCT from an active management protocol that included oxytocin made very little difference regarding the proportion of severe PPH.165

The WHO now regards CCT as optional when skilled healthcare professionals are assisting the deliveries and recommend against it when they are not. CCT remains to be recommended for caesarean deliveries, in cases where the placenta takes more than 30 minutes to deliver, and if ergot alkaloids are used as the prophylactic uterotonic.10

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2.2 TREATMENT OF POSTPARTUM HAEMORRHAGEThere is less of a consensus from national and international guidelines on the recommended therapeutic options for the treatment of PPH, once it has occurred. Guidance on specific uterotonics and prothrombotic agents for managing PPH is summarised in Table 5.

Table 5. International and country recommendations for the treatment of postpartum haemorrhage

Guidelines Uterotonics Prothrombotics

WHO (2012)10 • IV oxytocin alone is the recommended uterotonic drug for the treatment of PPH

• If IV oxytocin is unavailable, or if the bleeding does not respond to oxytocin, the use of IV ergometrine, oxytocin-ergometrine fixed dose, or a prostaglandin drug (including sublingual misoprostol, 800 mcg) is recommended

• The use of tranexamic acid is recommended for the treatment of PPH if oxytocin and other uterotonics fail to stop bleeding or if it is thought that the bleeding may be partly due to trauma

FIGO (2012)14 • Oxytocin is the preferred uterotonic, administered as 10 IU IM or IV infusion (20–40 IU in 1000 mL, 40 drops/minute; followed by 20 IU in 1000 mL, 40 drops/minute until haemorrhage stops)

• Ergometrine or methylergometrine 0.2 mg IM or slow IV to be used if oxytocin is not available or if bleeding continues despite having used oxytocin

• Syntometrine (combination of oxytocin 5 IU and ergometrine 0.5 mg) administered IM

• Single 800 mcg dose of sublingual misoprostol, if oxytocin is not available or administration is not feasible

• Carbetocin: 100 mcg IM or IV over 1 minute• Carboprost: 0.25 mg IM every 15 minutes

(maximum 2 mg)


SOGC (2009)13 • Since the most common cause of PPH is uterine atony, the clinician’s initial efforts should be directed at preventing ongoing blood loss by performing the initial basic manoeuvres of uterine massage and administering additional uterotonics, which include the following:

• Oxytocin 10 IU IM, 5 IU IV bolus or IV infusion (20–40 IU in 250 mL, hourly rate of 500 to 1000 mL)

• Carboprost 250 mcg IM or intramyometrially• Carbetocin 100 mcg IM or IV over 1 minute. Shown

to reduce bleeding due to uterine atony in caesarean sections but not low-risk vaginal deliveries

• Misoprostol (off-label use not approved for PPH by Health Canada)– 400 to 800 mcg. Onset of effects is faster with oral

or sublingual than with rectal administration– 800 to 1000 mcg. Effects are longer lasting with

rectal than with oral administration– Higher incidence of pyrexia with oral than with

rectal administration• Ergonovine 0.25 mg IM or IV

• Evidence for the benefit of rFVIIa has been gathered from very few cases of massive PPH. Therefore, this agent cannot be recommended as part of routine practice

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Table 5. continued

Guidelines Uterotonics Prothrombotics

CENETEC, Mexico (2008)12

• Recommends the use of uterotonic IM or IV as first-line treatment for PPH, using oxytocin alone or in combination with ergonovine


Polish Society of Gynaecologists (2013)141

• No specific guidance • No specific guidance

Queensland Maternity and Neonatal Clinical Guidelines Program (Australia) (2012)44

• First line:– Oxytocin 5 IU slow IV bolus over 1–2 minutes. Start

IV infusion of oxytocin 40 IU/1 1000 mL of crystalloid solution at a rate of 125–250 mL/hour (5–10 IU/hour)

– Ergometrine 250 mcg slow IV bolus over 1–2 minutes or IM injection

– Misoprostol 800–1000 mcg, rectally• Second line:

– Carboprost 250 mcg IM or intramyometrially

• rFVIIa is considered off licence and is not recommended for general use

• The decision to use rests with the clinician prescribing and requires practice review

RCOG (2009)11 The following in priority order:1. Oxytocin 5 IU slow IV bolus2. Ergometrine 0.5 mg slow IV bolus or IM injection3. Oxytocin IV infusion (40 IU in 500 mL, 125 mL/hour)4. Carboprost 250 mcg IM5. Carboprost 250 mcg intramyometrial injection, with

responsibility of the administering clinician as it is not recommended for intramyometrial use

6. Misoprostol 1000 mcg, rectally

• rFVIIa therapy should be based on the results of coagulation

• In the face of life-threatening PPH, and in consultation with a haematologist, rFVIIa may be used as an adjuvant to standard pharmacological and surgical treatments

ACOG (2006)75 • Oxytocin 10 IU IM or IV infusion (10–40 units in 1000 mL)

• Methylergometrine 0.2 mg IM• Carboprost 250 mcg IM• Dinoprostone 20 mg vaginal or rectal suppository• Misoprostol 800–1000 mcg, rectally

• IV dosages vary by case and generally range from 50 to 100 mcg/kg every 2 hours until haemostasis is achieved

• Additional clinical experience in all specialties will help determine rFVIIa’s role in the treatment of PPH

ACOG=American College of Obstetricians and Gynecologists; CENETEC=National Center for Health Technology Excellence (Mexico); FIGO=International Federation of Gynaecology and Obstetrics; IM=intramuscular; IV=intravenous; PPH=postpartum haemorrhage; RCOG=Royal College of Obstetricians and Gynaecologists; rFVIIa=recombinant activated factor VII alpha; SOGC=Society of Obstetricians and Gynaecologists of Canada; WHO=World Health Organization

2.2.1 Uterotonic agentsCurrent guidelines widely agree that oxytocin remains the first-line pharmacotherapy for managing PPH as well as for its prevention.23 The order of subsequent interventions is less clear: the FIGO, WHO and ACOG guidelines do not specify a preferred order for second-line medications,10,14,75 while the RCOG recommend a sequence of first-line slow IV bolus of oxytocin followed by ergometrine, oxytocin IV infusion, carboprost administered IM, intramyometrial carboprost and misoprostol given rectally (Table 5).11 Considerably fewer trials of uterotonics have been conducted for PPH treatment than for PPH prevention.

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A recent Cochrane review analysed 10 randomised clinical trials covering 4052 women in total, comparing the use of different uterotonic agents and other interventions for the treatment of PPH.166 Although the clinical trials included were not adequately powered to assess the impact on the primary outcome measures of the analysis, it was observed that, compared with misoprostol, oxytocin infusion was more effective and caused fewer side effects when used as first-line therapy for the treatment of primary PPH. Misoprostol appears to be less efficacious than oxytocin since significantly more women in the misoprostol group presented with blood loss ≥1000 mL (RR 2.65 [95% CI: 1.04, 6.75]; p=0.041) and required blood transfusion (RR 1.47 [95% CI: 1.02, 2.14]; p=0.04), compared with those in the oxytocin group.166

The addition of misoprostol to other uterotonics does not appear to confer a significant advantage over uterotonics used with placebo in terms of the rates of maternal mortality, hysterectomy or serious morbidity.166 Moreover, misoprostol was associated with significantly higher rates of adverse events, including vomiting (RR 1.84 [95% CI: 1.16, 2.95]; p=0.01), shivering (RR 2.25 [95% CI: 1.76, 2.88]; p<0.00001) and maternal pyrexia of at least 38°C (RR 3.12 [95% CI: 2.66, 3.67]; p<0.00001).166

Injectable prostaglandins are widely considered to be second-line medications for the treatment (and not for the prevention) of PPH.23 Carboprost tromethamine is a synthetic 15-methyl analogue of PGF2α that has been shown to more potently stimulate uterine myometrial contractility than naturally-occurring PGF2α.167 As a treatment for PPH, carboprost tromethamine is considered to be a second-or later-line therapy option after conventional methods have failed.11,14,44 There are very few studies evaluating the use of carboprost tromethamine in PPH management.27

2.2.2 Prothrombotic agentsTranexamic acid is widely used in major surgery to prevent fibrinolysis and to reduce surgical blood loss.168 A single randomised open-label trial has been carried out for the treatment of PPH, demonstrating that women who received tranexamic acid experienced significantly lower blood loss (median 170 vs 221 mL; p=0.041) and significantly shorter duration of bleeding versus placebo.169 Bleeding was successfully stopped in 63% of women on tranexamic acid compared with 46% in the control group (p=0.034), and there was a reduction of 27% in the proportion of women who progressed to severe PPH (p=0.028).169

Recombinant activated factor VII (rFVIIa) is another treatment for major bleeding that has been used off-label for PPH refractory to other treatments.170 rFVIIa is proposed to induce haemostasis by enhancing thrombin generation on thrombin-activated platelet surfaces, thereby providing the formation of a stable fibrin clot, which is resistant to premature fibrinolysis.170 Although a success rate of 68–84% has been reported in case series and registries,171,172 there are currently no clinical trials evaluating rFVIIa for the treatment of PPH. In addition, it is a high-cost drug with uncertain cost-effectiveness as a life-saving treatment.173 In light of this, current WHO guidelines state that there is insufficient evidence to recommend the use of rFVIIa for the treatment of PPH.10

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2.2.3 Non-pharmacological interventions: balloon devices and surgery

After failure of medical intervention to stop or reduce PPH, internal uterine tamponade can be considered. This process involves plugging the uterus with a device to stop the flow of blood, such as a gauze pack or a balloon catheter.174 Different balloon devices that can be used include the Sengstaken–Blakemore tube, the Bakri balloon, the Rusch balloon, Foley catheters and the condom catheter balloon; these approaches appear to be an effective tool for the management of PPH.175 The current WHO guidelines recommend the use of intrauterine balloon tamponade for refractory bleeding or if uterotonics are unavailable.10 Similarly, FIGO guidelines recommend balloon tamponade as a potentially life-saving procedure if bleeding persists after the administration of uterotonics.14

If bleeding does not stop, despite treatment using uterotonics and other available conservative interventions (e.g. uterine massage, balloon tamponade), the use of surgical interventions is recommended by the WHO guidelines. Conservative surgical approaches, such as compression sutures, should be attempted first. Should these fail, utero-ovarian and hypogastric vessel ligation can be used. If life-threatening bleeding continues even after ligation, then a subtotal or total hysterectomy should be performed.10

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KEY POINTS Active management of the third stage of labour is a key

component of PPH prevention, and is associated with a significantly reduced incidence of PPH compared with expectant management5

Oxytocin is the most frequently used uterotonic agent for the prevention of PPH.93,144 However, the label from a number of European countries recommends several routes of administration and dosages, including IV and IM injections. When considering IV administration, the recommendations include giving a 5 IU dose over 5 minutes (UK)33 or for more than 5 minutes (France),35 dissolving 10–40 IU in 1000 mL of non-moisturising solvent and infusing at a rate necessary to control uterine atony (Spain),31 administering 5 IU as a slow IV infusion (Italy)32 and as a 5–6 IU IV infusion (no rate specified).34 Similarly, several methods of administration (e.g. IM injection or prolonged IV infusion of 4-, 6-, 8- and 16-hours) and doses are used in routine practice, as well as in clinical trials10,11,13,14,36–45

Carbetocin is a synthetic, long-acting, analogue of oxytocin and the only approved room temperature-stable uterotonic for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia. It has a similar onset of action as oxytocin when administered by IV (1.2 minutes versus an almost immediate effect)55,57 or IM (approximately 2.5 minutes for both),55,56 but has a longer half-life in women (40 minutes for carbetocin vs 3–5 minutes for oxytocin)58–60 and thus a longer duration of action when given as an IM injection (119 vs approximately 30 minutes)55,56

Recent updated guidelines recommend the administration of uterotonics as part of the active management of the third stage of labour, whereas there is less consensus on the timing of cord clamping and the use of CCT, which are both initiated by the discretion of the clinician23

35

The SOGC guideline recommends carbetocin over continuous IV infusion of oxytocin as first-line therapy for PPH prevention in elective caesarean deliveries.13 The Danish Society of Obstetrics and Gynecology recommend carbetocin for PPH prevention as an alternative to oxytocin in high risk women (twins, multipara, previous PPH and coagulation disorders) for both caesarean section and vaginal delivery.143 The National Center for Health Technology Excellence in Mexico states that carbetocin (IV dose of 100 mg in 1 mL given over 1 minute) can be used instead of continuous infusion of oxytocin for elective caesarean section.12 Similarly, the Queensland Maternity and Neonatal Clinical Guidelines Program recommend that substitution of oxytocin infusion with carbetocin (IV dose of 100 mg in 1 mL administered over 1 minute) can be considered in elective caesarean delivery.44 The Polish Society of Gynaecologists and Ministry of Health of the Russian Federation evaluate carbetocin as an effective therapeutic option in elective caesarean sections, albeit without explicitly recommending it as first-line option.141,142 The Polish Society of Gynaecologists also advocate the use of carbetocin for uterine atony in vaginal deliveries.141 In addition, both the Philippine Obstetrical and Gynecological Society, and the Chinese Society of Obstetrics and Gynecology recommend the use of carbetocin as an alternative uterotonic, without specifying mode of delivery.16

Ergot alkaloids are less effective than oxytocin for the prevention of PPH and are also associated with more side effects26,29

Use of prostaglandin analogues (misoprostol, sulprostone and carboprost) for the prevention of PPH should be reserved for circumstances where safe administration or appropriate storage of other uterotonic agents is not possible.158 However, they can be used for the treatment of PPH when prevention fails11,14,23,44

Oxytocin is regarded as the first-line pharmacotherapy to treat PPH once it has occurred10–12,14,16,23,44

Balloon tamponade techniques are moderately successful at stopping serious haemorrhage if pharmacological options fail174

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3.1 RATIONALE FOR THE DEVELOPMENT OF CARBETOCIN AND ITS NEW HEAT-STABLE FORMULATION

3.1.1 Need for a uterotonic agent with consistent dosage and method of administration

Oxytocin is currently the mainstay of therapeutic intervention in the active management of the third stage of labour to prevent uterine atony and thus PPH.23 However, there is no consistent administration method or dose indicated amongst the label from some European countries (UK, France, Italy, Spain and Germany), which include IM and IV injections and doses ranging 5–40 IU.31–35 When considering the IV route, both the UK and French labels recommend administering 5 IU of oxytocin preferentially using a variable-speed infusion pump, either over 5 minutes (UK)33 or for more than 5 minutes (France).35 By contrast, the Spanish label indicates dissolving 10–40 IU of oxytocin in 1000 mL of non-moisturising solvent and infusing at a rate necessary to control uterine atony,31 while the label in Italy recommends 5 IU slow IV infusion,32 and Germany advocates 5–6 IU IV infusion without specifying the rate.34

Similarly, several methods and dosages have also been used in clinical practice (see Section 2.1.2.1)36–43 and are recommended by several major international and local guidelines.10,11,13,14,44 Among these different administration routes, prolonged IV infusions of 4, 6, 8 and 16 hours are used.13,37–41,45 When a drug is administered via a prolonged IV infusion, clinical staff require appropriate training and need to regularly monitor their patients throughout the IV infusion.47,48 The MHRA investigated 1085 incidents involving infusion pumps over a 5-year period (2005 to 2010) and published their findings, which highlighted the importance of reporting adverse events, and the need for formalised and validated competence-based training when considering the use of infusion pumps.46 A study monitoring IV infusion of acetylcysteine, which requires administering three consecutive doses (150 mg/kg for 15 minutes, 50 mg/kg for 4 hours and 100 mg/kg for 16 hours), identified differences of ≥50% between the measured and predicted dose values, indicating major errors in dose calculation or preparation of the drug. Substantial differences between pre- and post-infusion solution were also observed, suggesting inappropriate mixing.176

3.1.2 A good safety profile is the key consideration for any uterotonic agent

Medication errors are the most frequent cause of adverse events.49–51 Drugs that have higher risks of causing significant patient harm when used in error are called ‘high-alert medications’. Since 2007, IV oxytocin has been on the list of high-alert medications released by the Institute for Safe Medical Practices.52 Errors related to IV administration of oxytocin are mainly dose related.53,54

CHAPTER III

37

Moreover, oxytocin has recognised antidiuretic effects,177 and thus its IV infusion may cause water intoxication, a form of acute hyponatraemia. The first report dates back to 1962178 and in 1975 a review reported 23 cases.179 The problem has been described in women treated with oxytocin for PPH,180–182 induction or augmentation of labour,183–187 and abortion.179,188–190 The risk of hyponatraemia associated with oxytocin is increased when it is administered in a 5% dextrose solution in water (which does not contain electrolytes) and when high-dose (exceeding 20 mU/minute) oxytocin infusions are used. Clinical signs and symptoms of hyponatraemia include confusion, convulsions, coma, congestive heart failure and even death. Consequently, total fluid intake of patients receiving oxytocin should be strictly monitored as there should be a significant difference between liquid intake and output before development of hyponatraemia.191 Since the fetus takes water from the maternal circulation via the placenta, the newborn infant of a hyponatraemic mother also has a considerable risk of developing water intoxication.184,186,187,192,193

The antidiuretic effects of oxytocin add to an already increased risk of developing hyponatraemia due to natural physiological factors associated with pregnancy and labours, such as: osmoregulatory changes,194,195 impaired ability to excrete a water load during labour,196 and increased secretion of antidiuretic hormone during labour (due to pain, emotional stress and nausea).192 Thus, hyponatremia is a pathological condition that should be carefully considered in pregnant women.

The observed antidiuretic effects of oxytocin can be explained by its high structural similarity with vasopressin (also known as antidiuretic hormone). Both are neurohypophysial hormones synthesised by the magnocellular neurons of the hypothalamus and are cyclic nonapeptides with a disulfide bridge between cysteine residues at positions 1 and 6.197,198 Their structures are similar and differ only by two amino acids at position 3, in the cyclic part of the peptide, and 8 (Figure 3).199 Vasopressin is involved in regulation of water reabsorption and concentration of the urine, control of blood pressure and stimulation of adrenocorticotrophic hormone (ACTH),200,201 while oxytocin plays a key role in parturition, lactation and sexual behaviour.198

Oxytocin

1 2 3 4 5 6 7 8 9

Vasopressin

1 2 3 4 5 6 7 8 9

Cys - Tyr - Ile - Gln - Asn - Cys - Pro - Leu - Gly - NH2

Cys - Tyr - Phe - Gln - Asn - Cys - Pro - Arg - Gly - NH2

Disulphide bond S–S


A

B

Figure 3. Amino acid sequence of oxytocin (A) and vasopressin (B)

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In addition to their resemblance at the molecular structure level, oxytocin and vasopressin exert their physiological activities by binding to a specific receptor sub-family within the large superfamily of G-protein coupled receptors. Vasopressin acts on three receptor subtypes: vasopressin V1a (liver, smooth muscle cells from blood vessels, and central nervous system), vasopressin V1b (anterior pituitary) and vasopressin V2 (kidney).200,201 Only one oxytocin receptor, expressed in the uterus, mammary gland and central nervous system, has been cloned so far.202

Vasopressin V1a receptors are found in a variety of body tissues and they mediate diverse biological effects, including hypotension-induced vasoconstriction, gluconeogenesis and platelet aggregation.200 The vasopressin V1a receptor is also expressed in the brain, where vasopressin acts as a neuromodulator/neurotransmitter regulating an array of central nervous system-mediated functions (e.g. learning and memory, neuroendocrine reactivity, social behaviours, circadian rhythmicity, thermoregulation and autonomic function).203 Vasopressin V1b receptors are present in the anterior pituitary and mediate the ACTH-releasing effects of vasopressin.199 Vasopressin V2 receptors are present in the collecting duct of the kidney, and mediate the antidiuretic action of vasopressin.200

Oxytocin is known to have an antidiuretic effect,177 but the underlying molecular mechanisms are not completely understood. However, oxytocin has been shown in vitro to increase osmotic water transport in micro-dissected renal inner medullary collecting ducts; this effect was not altered by two different oxytocin receptor antagonists.204 In an in vivo animal study, oxytocin caused marked antidiuresis in vasopressin-deficient Brattleboro rats and increased expression of aquaporin-2, a water channel that mediates vasopressin effects. These outcomes could be reversed by a vasopressin V2 receptor antagonist, but not by an oxytocin receptor antagonist. All these findings suggest that oxytocin stimulation of vasopressin V2 receptors may mediate the antidiuretic effects of oxytocin.205

3.1.3 Alternative uterotonic agents to oxytocin for PPH prevention have shown some limitations

Other uterotonic agents have been used to prevent PPH, but these have shown reduced efficacy and/or safety. Ergot alkaloids are an injectable class of uterotonic agents, but demonstrate lower efficacy and are less well-tolerated, compared with oxytocin.26,29 Syntometrine, the combination of ergometrine maleate and oxytocin, when compared to oxytocin is associated with a small, but significant, reduction in the risk of PPH when considering blood loss of 500 mL or more; no difference was observed between the groups for blood loss of 1000 mL or more. However, syntometrine also shows a statistically significant increase in the risk of maternal side effects, including elevated blood pressure, nausea and vomiting.153 The limited data available for PGE2 point towards a similar efficacy as oxytocin, but with an unfavourable safety profile.27,30 Oral misoprostol is easy to administer compared with IV uterotonics and does not require refrigeration, but it is less effective than oxytocin in preventing PPH28 and is generally not licensed for PPH prevention (exceptions include India, Nepal, Bangladesh, Ghana, Kenya, Nigeria, Sudan, Tanzania, Uganda and Zambia).206 Furthermore, misoprostol leads to more side effects, such as shivering and pyrexia,27,28 and is associated with a higher risk of severe PPH and increased use of additional uterotonics, compared with oxytocin.27

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3.1.4 Need to overcome refrigerated storage conditionsFor optimum use in the prevention or treatment of PPH, oxytocin must be stored under refrigerated conditions207 owing to degradation at higher temperatures.208 However, in resource-poor countries, the cold-chain facilities required for the transport and storage of oxytocin are unreliable.209 Although recent efforts have been conducted to develop a heat-stable oxytocin formulation,208,210 this is, so far, not available for therapeutic use. Ergot alkaloids have also demonstrated instability when stored under conditions simulating tropical climates,211 potentially limiting their use in such regions. Similarly, the previous formulation of carbetocin needed to be stored in a refrigerator at temperatures between 2°C and 8°C.61

All the considerations described in Section 3.1 clearly outline the unmet need for an effective and well-tolerated uterotonic medication that:

• Is long acting and thus does not require prolonged IV infusion

• Is administered via a single IV injection, with no need for repeated injections

• Has a well established dose that has been validated for the prevention of PPH in randomised clinical trials, and recommended and used consistently

• Is stable at room temperature

• Has lower affinity to the vasopressin V2 receptor compared with oxytocin

This led to the development of carbetocin, a long-acting analogue of oxytocin, which is now available in a heat-stable formulation (see Section 3.2).

3.2 CARBETOCIN PROPERTIES

3.2.1 Indications, clinical properties and guideline recommendations

Carbetocin is a long-acting structural analogue of naturally-occurring human oxytocin, with a half-life of approximately 40 minutes.58 It is indicated for the prevention of uterine atony following delivery of the infant by caesarean section under epidural or spinal anaesthesia.61 It is also approved for the prevention of uterine atony in women at risk of PPH following vaginal delivery in several countries (including to date Russia, Mexico, Kazakhstan, Cuba, Ecuador, El Salvador and Honduras)72–74 and for the treatment of uterine atony in Mexico.74

One vial contains 100 mcg of carbetocin in 1 mL solution for injection, which must be administered slowly over 1 minute in a single IV injection, under adequate medical supervision in a hospital. It should be given as soon as possible after the birth of the baby and, preferably, before removal of the placenta.61 Carbetocin is also approved for IM administration into the upper thigh in several countries, including Russia, Mexico and Kazakhstan.73,74

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In women undergoing caesarean section, carbetocin is equally effective as oxytocin in reducing the risk of PPH or severe PPH, and has a comparable adverse event profile.45,62–65 However, carbetocin significantly reduces the need for additional uterotonics and uterine massage compared with oxytocin.62 Even when they are required, the time before further uterotonic treatment is significantly longer in women administered with carbetocin than in those treated with oxytocin.63 Blood loss ≤500 mL is higher in women treated with carbetocin compared with oxytocin (81 vs 55%; p=0.05).64 Evidence from one clinical study also indicates that carbetocin is associated with significantly lower levels of perceived post-operative pain following caesarean delivery than oxytocin.66

Compared with syntometrine, carbetocin has shown similar levels of additional uterotonic use, but a significant reduction in mean blood loss.62 Moreover, women treated with carbetocin have been shown to experience less nausea, vomiting, tremor, post-delivery hypertension and uterine/abdominal pain than those treated with syntometrine. The clinical trial results for carbetocin are reviewed in detail in Chapter IV.

In light of these advantages over oxytocin (significantly reduced need for additional uterotonic treatment and uterine massage, significantly increased time before further uterotonics, and higher incidence of blood loss ≤500 mL, alongside data from one study indicating a significantly lower post-operative pain)45,62–66 and syntometrine (significant reduction in mean blood loss and superior safety profile),62 carbetocin has been recommended by the SOGC as the first-line therapy for preventing uterine atony in women undergoing elective caesarean section.13 The Danish Society of Obstetrics and Gynecology recommends carbetocin for PPH prevention as an alternative to oxytocin in high risk women (twins, multipara, previous PPH and coagulation disorders) for both caesarean sections and vaginal delivery.143 Clinical guidelines from the National Center for Health Technology Excellence in Mexico and the Queensland Maternity and Neonatal Clinical Guidelines Program also affirm that carbetocin is an effective therapy for preventing uterine atony and can be used (Mexico) or considered for use (State of Queensland) instead of continuous infusion of oxytocin in women delivering by elective caesarean section.12,44

The Ministry of Health of the Russian Federation and the Polish Society of Gynaecologists are very positive towards carbetocin and evaluate it as an effective therapeutic option for preventing PPH in caesarean section.141,142 The latter also favours the use of carbetocin for preventing uterine atony in women delivering vaginally, and recommends that it should be available in “each delivery room and operating theatre”.141 Furthermore, guidelines released by the Philippine Obstetrical and Gynecological Society, and the Chinese Society of Obstetrics and Gynecology propose the application of carbetocin as an alternative uterotonic agent, without specifying mode of delivery.16

3.2.2 Room temperature-stable formulationBoth oxytocin and ergot alkaloids need to be stored under refrigerated conditions, which can be an issue for low-income countries where cold-chain storage and transport may not be available.209

To fulfil this unmet need, a new room temperature-stable formulation of carbetocin has now been developed. Based on the results obtained in stability studies, this formulation has a shelf-life of 24 months at 30ºC and 75% humidity.212

The new room temperature-stable formulation is also provided in a vial, as opposed to the ampoule used for the original carbetocin formulation. This is expected to be more convenient for clinicians and to decrease the risk of lacerations from broken ampoules.

41

3.2.3 Potency at the vasopressin V2 receptorThe antidiuretic effects of oxytocin177 mean that infusions of the drug, especially when administered in a solution that does not contain electrolytes (e.g. 5% dextrose solution) or at a high dose (>20 mU/minute), may lead to hyponatraemia.191 The condition has been reported in women undergoing oxytocin treatment for PPH,180–182 induction or augmentation of labour,183–187 and abortion,179,188–190 as well as in newborn infants delivered from hyponatraemic mothers.184,186,187,192,193

Vasopressin V2 receptors are found in the collecting duct of the kidney, and mediate the antidiuretic action of vasopressin.200 Indeed, in vitro204 and in vivo animal studies205 have suggested that oxytocin-mediated antidiuretic activity is exerted via the vasopressin V2 receptors.

To date, no cases of hyponatraemia have been reported in the literature for carbetocin, although an antidiuretic effect cannot be completely excluded given the similarity in molecular structure between carbetocin and oxytocin (Figure 4).61 To create carbetocin, several modifications were made to the oxytocin molecule, specifically the amino group (NH2) in cysteine has been replaced with a hydrogen atom, the disulphide bond has been changed to a thio-ether bond (CH2S), and the hydroxyl group (OH) of tyrosine has been substituted by a methyl ether group (Figure 5A).58 The carbetocin molecule (Figure 5B) is therefore more resistant to aminopeptidase (no NH2 group in cysteine) and disulphidase (no disulphide bridge) cleavage. Together, these alterations reduce the chance of enzymatic degradation and prolong the half-life of the peptide thus extending its pharmacological action.58

Oxytocin

Cys - Tyr - Ile - Gln - Asn - Cys - Pro - Leu - Gly - NH2 1 2 3 4 5 6 7 8 9

Carbetocin

CH2 - CH2 - CH2 - CO - Tyr - Ile - Gln - Asn - Cys - Pro - Leu - Gly - NH2

OMe

1 2 3 4 5 6 7 8


Thio-ether bond CH2–S

A

B

Figure 4. Amino acid sequence of oxytocin (A) and carbetocin (B)

42

Carbetocin

OxytocinA

B

Substitutedwith CH2

Substituted with ahydrogen atom

Substitutedwith methylether group

Figure 5. Modifications made to the oxytocin structure (A) to create the synthetic long-acting analogue carbetocin (B)

Figure adapted from Cordovani et al. (2013)213

43

The structural differences between carbetocin and oxytocin may also influence receptor binding and potency. Indeed, it has been demonstrated in vitro that carbetocin is much less potent, and thus more selective, than oxytocin at the human vasopressin V2 receptor (EC50: 170 vs 7nM).214 Despite the different selectivity displayed in vitro, the possibility of hyponatraemia cannot be excluded, particularly in patients also receiving large volumes of intravenous fluids.74

3.3 MECHANISM OF ACTIONOnce the placenta has separated from the myometrium during the third stage of labour, the resulting bleeding is controlled by the contraction and retraction of the uterine smooth muscle fibres surrounding maternal arteries in the placental bed.109 This contraction is sufficient to compress the arterial walls completely, eliminating the arterial lumina and stopping blood flow.109

The endogenous hormone oxytocin is a key trigger for uterine myometrial contraction, exerting its effects by binding to oxytocin receptors in the uterine smooth muscle. A progressive increase in uterine contractility and oxytocin sensitivity is observed throughout the course of pregnancy.215 In line with these observations, the expression of oxytocin receptors in the myometrium increases during the late gestational period (>36 weeks).216

The oxytocin receptor belongs to the G-protein coupled receptor superfamily, and is able to couple with multiple guanosine triphosphate-binding proteins (G-proteins) that activate different intracellular pathways. In the uterus, binding of ligand to the oxytocin receptor activates the G-protein, Gαq/11, which in turn stimulates phospholipase C that controls the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. These two second messengers have further downstream effects: IP3 is responsible for the release of calcium from intracellular stores, while diacylglycerol activates protein kinase C, a pivotal enzyme that phosphorylates other proteins. Free calcium released from intracellular stores bind to calmodulin and the resulting calcium–calmodulin complex activates the myosin light-chain kinase, which leads to cross-bridge formation between myosin and actin, and thus smooth muscle contraction. The free calcium from intracellular stores also contributes towards changes in charge potential on the cell membrane, resulting in the opening of voltage-operated calcium channels that facilitate the entry of extracellular calcium into the muscle cell. In addition, the intracellular stores (as they are depleted of calcium) and the increase in IP3 and diacylglycerol levels, elicit an influx of extracellular calcium by activating store-operated calcium channels on the cell membrane; however, the precise mechanism remains unclear (Figure 6). Once inside the smooth muscle cell, the extracellular free calcium acts in the same way as free calcium released from intracellular stores to activate muscle contraction.145

44

Carbetocin binds to oxytocin receptors on the myometrial plasma membranes with receptor affinities in the same order of magnitude as the endogenous hormone, oxytocin, and has the pharmacological profile of a long-acting oxytocin agonist.149,150 A single IV dose of carbetocin 100 mcg administered after the delivery of the baby is sufficient to maintain adequate uterine contraction, preventing uterine atony and excessive bleeding with an efficacy comparable to several hours of oxytocin infusion.45

3.4 PRE-CLINICAL STUDIESPre-clinical work on the pharmacological activity of carbetocin in vitro showed that carbetocin exerted a contractile effect on isolated uterine myometrial strips from rats.150 These results were subsequently replicated in vitro with uterine tissue from both rats and horses.149,217

The in vitro studies confirmed that oxytocin and carbetocin have similar binding affinities at the oxytocin receptor.149,150 However, carbetocin has an EC50 (the concentration at which half of the maximal response is achieved) approximately ten times that of oxytocin (5.62 ± 1.22 vs 48.0 ± 8.20 nM) and triggers contractions that are approximately half as strong (2.70 ± 0.12 vs 5.22 ± 0.26 g) (Figure 7). Two metabolites of carbetocin, desGlyNH2-carbetocin and desLeuGlyNH2 carbetocin, were shown to induce no contractile activity.149

C

CC

CC

CCarbetocin Calcium Oxytocin receptor

on uterine smoothmuscle

Voltage-operatedcalcium channel

IP3 and diacylglycerol

CalmodulinMyosin

light-chainkinase

Uterinecontractions

Intracellular calcium stores

Store-operated calcium channel

Figure 6. Carbetocin binds to oxytocin receptors and triggers the release of intracellular calcium145

Figure adapted from Arrowsmith and Wray (2014).145 Receptor binding triggers activation of phospholipase C and the generation of the second messengers, IP3 and diacylglycerol. IP3 induces release of free calcium from intracellular stores, which bind to calmodulin and stimulates uterine smooth muscle contractions via activation of myosin light-chain kinase. The elevation in intracellular free calcium triggers voltage-operated calcium channels, while increased levels of IP3 and diacylglycerol, and signals originating from the calcium-depleted intracellular stores activate store-operated calcium channels on the cell membrane. These events cause an influx of extracellular calcium that stimulate uterine smooth muscle contractility;145 IP3=inositol 1,4,5-trisphosphate

45

6

4

2

0

Peptide concentration (M)

10–710–810–910–10 10–510–6 10–4

Cont

ract

ile r

espo

nsiv

enes

s (g

) OxytocinCarbetocindesGlyNH2-carbetocindesLeuGlyNH2-carbetocin

Figure 7. The contractile response of carbetocin is about half as strong as that of oxytocin, whereas neither desGlyNH2-carbetocin nor desLeuGlyNH2-carbetocin demonstrated contractile activity on isolated rat uterine strips149

However, one study showed that, despite the low biological activity, the response was more prolonged with carbetocin than with oxytocin and could not be abolished by washing of the uterine strips with buffer solution.150 The authors thus concluded that the longer half-life of carbetocin at the receptor compartment may be a contributing factor to the prolonged uterotonic effect observed in vivo (see Section 3.5.2).150

3.5 CLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS OF CARBETOCIN

3.5.1 Overview of the clinical studiesThe pharmacokinetics and pharmacodynamics of carbetocin have been assessed in several small studies with pregnant and non-pregnant women. Inclusion/exclusion criteria for the pharmacokinetic and pharmacodynamic studies of carbetocin are shown in Table 6 and Table 7, respectively.55,58,218

Data are mean ± standard error

46

Table 6. Inclusion/exclusion criteria for the two pharmacokinetic studies

Trial Study design Inclusion criteria Exclusion criteria

Sweeney et al (1990)58

Pharmacokinetics study

• Non-pregnant women• Aged 18–36

• Liver, renal or endocrine disease• Abnormal electrocardiograms• Taking medications other than oral

contraceptives, vitamins or iron medications

FE 992097 000146219 Bioavailability study

• Non-pregnant women• Aged 18–45 years• BMI 19–29 kg/m2

• Negative virology/serology result for HIV-1 and HIV-2, hepatitis B surface antigen, and hepatitis C virus at screening

• Systolic blood pressure 90–145 mmHg

• Diastolic blood pressure 60–95 mmHg

• Pulse 45–100 bpm• Negative urine drug

screen, and alcohol breath test

• Non-smoker or light smoker (<5 cigarettes, or equivalent, per day)

• Agree to use adequate contraception during study

• History or evidence of renal, hepatic, gastrointestinal, respiratory, cardiovascular or musculoskeletal diseases

• History or evidence of migraine, epilepsy and seizures

• Any medical or surgical condition that could interfere with absorption, distribution, metabolism, or excretion of study drug, as judged by investigator

• History of cancer, other than adequately-managed basal cell carcinoma and squamous cell carcinoma of the skin, within last 5 years

• History or evidence of severe allergy or anaphylactic reactions

• Acute illness within 2 weeks prior to screening

• Taking medication, other than hormonal contraceptives, paracetamol, ibuprofen, and cromoglycate, within 2 weeks or 5 half-lives of drug, whichever was longer, prior to first dosing

• History of hypersensitivity to any component of study drug

• History or present abuse of narcotics/recreational drugs or alcohol

• High daily consumption of caffeine-containing beverages (e.g. >5 cups of coffee)

• Blood donation or major blood loss (>500 mL) within 60 days preceding first administration of study drug

BMI=body mass index; HIV=human immunodeficiency virus

47

PPH=postpartum haemorrhage

Table 7. Inclusion/exclusion criteria for the three pharmacodynamic studies


Hunter et al (1992)55 Pharmacokinetics study

• Women 24–48 hours after vaginal delivery at term (≥37 weeks gestation)

• Hypertension • History of cardiac, renal, or hepatic disease

van Dongen et al (1998)218

Dose-finding study

• Healthy women at low risk of PPH

• Normal singleton pregnancy

• Severe anaemia• Eclampsia• Antepartum haemorrhage• Prolonged labour• Intrapartum blood loss• History of PPH or retained placenta• Polyhydramnios• Multiple pregnancy• Previous difficult instrumental delivery• No epidural analgesia during labour

CLN 6.3.5220 Dose-finding study

• Healthy women undergoing elective caesarean section

• History of heart disease or hypertension• Abnormal pre-study laboratory parameters• Cardiac arrhythmia• History or evidence of liver, renal or

endocrine disease

3.5.2 Pharmacokinetic studies

3.5.2.1 Pharmacokinetic study: Sweeney et al. 199058

The pharmacokinetics of IV and IM carbetocin were studied in 25 healthy non-pregnant women between the ages of 18 and 36 years. Escalating doses of 0.05–0.8 mg were administered IV to the women and only those who received the highest two doses (0.4 and 0.8 mg) went on to receive the same dose as an IM injection 1–2 weeks afterwards.

The distribution half-life (Alpha-HL) and the elimination half-life (Beta-HL) of a 0.4 mg IV dose of carbetocin were found to be 5.54 ± 1.6 minutes and 41.0 ± 11.9 minutes, respectively. The equivalent figures for the 0.8 mg dose were 6.05 ± 1.15 minutes and 42.7 ± 10.6 minutes, respectively (Table 8). These are longer than the elimination half-life of oxytocin, which has been reported to be 3–5 minutes after a single 2 IU or 5 IU injection59,60 and 5 minutes following IV infusion of 2 IU at a rate of 500 mU/minute.60

IM administered carbetocin entered the circulation rapidly, with a time to peak concentration of less than 30 minutes (Table 8 and Figure 8). The absolute bioavailability of IM carbetocin was 76 and 83% for the 0.4 and 0.8 mg doses, respectively, making such a delivery method practical.

48

Carbetocin (0.4 mg IM bolus)

Carbetocin (0.8 mg IM bolus)

16000

14000

12000

10000

8000

6000

4000

2000

00 100 200

Time (minutes)

300 400

Plas

ma

carb

etoc

inco

ncen

trat

ion

(pcg

/mL)

Figure 8. Concentration-time curves for 0.4 and 0.8 mg intramuscular carbetocin in non-pregnant women58

Data are mean ± standard error; IM=intramuscular

Table 8. Key pharmacokinetic parameters for carbetocin in non-pregnant women58

ParameterIV injection IM injection

0.4 mg 0.8 mg 0.4 mg 0.8 mg

AUC0–inf (mcg•min/mL) MeanRange

749.2 ± 131.0539.5–916.9

1370.4 ± 214.91148.8–1733.0

553.5 ± 132.9403.3–733.7

1107.4 ± 56.51028.0–1181.4

Clt (L/min) MeanRange

0.549 ± 0.1050.436–0.741

0.595 ± 0.0890.462–0.696 – –

Clr (L/min) MeanRange

0.004 ± 0.0020.002–0.007

0.004 ± 0.0020.002–0.007 – –

Alpha-HL (min) MeanRange

5.54 ± 1.63.3–7.8

6.05 ± 1.155.1–8.2 – –

Beta-HL (min) MeanRange

41.0 ± 11.928.7–59.2

42.7 ± 10.639.3–49.4 – –

Cmax (mcg/L) MeanRange – –

6.35 ± 1.394.1–8.1

12.04 ± 1.889.4–14.7

Tmax (min) MeanRange – –

20.0 ± 0.020–20

28.0 ± 11.020–40

F (%) MeanRange – –

76.0 ± 10.860.8–84.8

83.4 ± 17.659.3–102.8

Data are mean values ± standard error. Alpha-HL=distribution half-life; AUC0–inf=area under the plasma concentration versus time curve from time 0 to infinity; Beta-HL=elimination half-life; Clt=total body clearance; Clr=total renal clearance; Cmax=maximum concentration; F=bioavailability; IM=intramuscular; IV=intravenous; Tmax=time to peak concentration

49

3.5.2.2 Bioavailability study: FE 992097 000146219

The bioavailability and pharmacokinetics of the room temperature-stable formulation of carbetocin were evaluated in 20 healthy non-pregnant women aged between 18 and 45 years. Each woman was randomly assigned to receive a single 100 mcg dose of room temperature-stable carbetocin administered as either IV or IM injection on Day 1, followed by 6 hours of pharmacokinetic sampling. After an overnight wash-out period, each woman was given the alternate injection on Day 2 and the 6-hour pharmacokinetic sampling repeated. Women were admitted to the study centre on Day 1 and remained on-site until the end of Day 2.

Of the 20 women, one had an abnormal pharmacokinetic profile, characterised by increasing plasma concentrations over 30 minutes, following IV injection of the study drug. By contrast, IM administration of room temperature-stable carbetocin in the same woman did not show any deviations from the expected pharmacokinetic profile. This suggested an irregularity during the IV administration process and thus the pharmacokinetic data derived from the IV injection period only for this individual were excluded from the final analysis.

Drug exposure (AUC0–inf and AUC0–t) was higher with IV versus IM injection of the 100 mcg dose of room temperature-stable carbetocin (AUC0–inf: 2.76 and 2.15 h•mcg/L; AUC0–t: 2.70 and 2.02 h•mcg/L, respectively). The terminal half-life (T½) was 33 minutes after IV administration and 55 minutes after IM injection (Table 9).

Room temperature-stable carbetocin reached peak concentrations at 30 minutes after IM injection (Table 9 and Figure 9), which is similar to that observed in a pharmacokinetic study with carbetocin that requires refrigerated storage.58 The absolute bioavailability of IM administered room temperature-stable carbetocin was high (77%) and comparable to previously reported data.58

Table 9. Key pharmacokinetic parameters for room temperature-stable carbetocin in non-pregnant women219

Parameter Carbetocin 100 mcg IV(n=19)

Carbetocin 100 mcg IM(n=20)

AUC0–inf (h•mcg/L) 2.76 2.15

AUC0–t (h•mcg/L) 2.70 2.02

Cmax (mcg/L) 7.23 1.03

T½ (min) 32.9 54.9

Tmax (min) – 30.0 (15–45)

All data are geometric mean values, except for Tmax which are represented as median and range; AUC0–infinity=area under the plasma concentration versus time curve from time 0 to infinity; AUC0–t=area under the plasma concentration versus time curve from time 0 to last sample with a quantifiable concentration; Cmax=maximum concentration; IM=intramuscular; IV=intravenous; n=number of women; T½=terminal half-life; Tmax=time to peak concentration

50

Carbetocin 100 mcg IM

Carbetocin 100 mcg IV10

9

8

7

6

5

4

3

2

1

0

Carb

etoc

in (n

g/m

L)

Time (hours)0 0.5 1 1.5 2 2.5 3 4 5 6

Figure 9. Concentration-time curves for room temperature-stable carbetocin in non-pregnant women219

IM=intramuscular; IV=intravenous

3.5.3 Pharmacodynamic studies

3.5.3.1 Dose-finding study: Hunter et al. 199255

A clinical pharmacodynamics study in 40 pregnant women who had vaginal deliveries was performed to determine the IM and IV doses of carbetocin required to produce sustained contraction of the uterus at 24–48 hours postpartum. Seventeen women were given repeated IV injections of carbetocin at 1-minute intervals until a tetanic uterine contraction occurred. A further 23 women were given single doses of carbetocin by IM injection.

Initial IV doses of 100 and 50 mcg produced severe abdominal cramps in two women, thus these two women did not receive subsequent lower doses of carbetocin and no tocographic records were obtained. For the remaining 15 women, the dose was reduced to either 2 or 10 mcg and was repeated until a tetanic uterine contraction was observed. Uterine tetany without significant side effects (e.g. cramping) was reported in 11/15 (73%) women: the lowest total dose was 8 mcg, whereas one woman achieved tetany only after a total dose of 30 mcg (Table 10). The onset of uterine activity after IV administration of carbetocin was rapid, occurring within 1.2 ± 0.5 minutes. Uterine tetany lasted 6.9 ± 2.1 minutes and the overall duration of uterine activity was 60 ± 18 minutes.

Based on the results of the IV injections, the initial IM dose was set at 10 mcg. Each woman received a single injection of 10–70 mcg and all 23 reported uterine contractions within 5 minutes, with a mean time of 2.3 ± 1.3 minutes. Analysis of tocographic records was possible for 10 women, revealing a mean time to first contraction of 1.9 ± 0.6 minutes. The overall duration of uteronic activity with IM carbetocin was significantly longer than that obtained with IV carbetocin (119 vs 60 minutes; p=0.02).

51

3.5.4 Dose-ranging studies

3.5.4.1 Dose-finding study: CLN 6.3.5220

This clinical dose-titration study in 18 women undergoing caesarean section aimed to determine the IV dose of carbetocin required to produce a tetanic uterine contraction after delivery of the placenta.

The trial protocol scheduled each woman to be given an initial starting dose between 10 mcg and 100 mcg of carbetocin, after which uterine tone was assessed visually and by manual examination of the uterus. Additional 10 mcg injections were administered at 1-minute intervals if a tetanic uterine contraction was not observed within 1 minute after injection. Dosing was stopped if no tetanic contractions were observed after 4 additional doses had been administered (that is, a total time of 5 minutes after the initial injection).

†woman experienced mild cramping 0.7 minutes after carbetocin injection, which continued for about 20 minutes; ‡woman reported cramping starting 2 minutes after the first injection and continuing for about 5 minutes after the last injection; §woman reported contractions starting 1 minute and 40 seconds after carbetocin injection, which lasted for 60 minutes

Table 10. Uterine tetany without significant side effects was observed in 11 out of 15 pregnant women administered a total intravenous dose of carbetocin ranging 8–30 mcg55

Woman’s reference number

Initial dose (mcg)

Increment dose (mcg)

Total dose (mcg)

Tetanic dose (mcg)

2346789

101415

10101010101010101010

10101010101010101010

20404020301010101010

20Mild cramp†

301010

Cramp‡

10101010

1112131617

22222

22222

10108

1210

1088

No tetanyContractions§

The duration of uterine activity for a single IV injection of 8–30 mcg carbetocin administered 24–48 hours postpartum in women who had normal vaginal deliveries was 60 minutes. When given as a single IM injection of 10–70 mcg, the duration of action was 119 minutes, which is approximately four times longer than that previously reported for a single IM injection of 5 IU oxytocin administered 48–72 hours postpartum in women with unspecified delivery (approximately 30 minutes).56 This characteristic of carbetocin may be attributed to an increased elimination half-life in plasma (40 minutes vs 5 minutes for oxytocin, as determined in non-pregnant women),58,59 and a longer half-life at the receptor compartment, as shown in in vitro studies of carbetocin on isolated uterine myometrial strips from rats.150

52

A total of 12 women received a starting dose between 10 mcg and 60 mcg carbetocin, and all required additional carbetocin to achieve a tetanic uterine contraction. The six remaining women received 100 mcg carbetocin, of whom five responded with tetanic contractions (Table 11). The sixth woman did not have tetanic contractions, but was assessed by the physician as having adequate tone and did not need further uterotonics.

Uterine tone after carbetocin administration was maintained throughout the duration of the study, which lasted for an average of approximately 9 hours; no woman required further oxytocic therapy due to rebound uterine atony. All women who received starting doses of ≤60 mcg required additional doses to achieve tetanic contraction, whereas none of those who received 100 mcg in the first instance needed further injections (Table 12). The authors thus determined that the optimum single dose of carbetocin is 100 mcg administered IV.

Few side effects were observed and none were serious (Table 13). All, but the two women who received a total dose of 30 mcg, had normal lochias and a normal rate of uterine involution throughout the duration of the study.

Table 11. Women who received a starting dose of 60 mcg or lower required additional dose administration220

Woman Starting dose (mcg)Number of additional

10 mcg doses administered Total dose (mcg)

1 100 0 100

2 10 3 40

3 10 2 30

4 20 1 30

5 20 1 30

6 30 2 50

7† 30 4 70

8 40 1 50

9 40 3 70

10 50 2 70

11 50 1 60

12 50 1 60

13 60 3 90

14 100 0 100

15 100 0 100

16 100 0 100

17 100 0 100

18 100 0 100

†Woman had a firm, rather than tetanic contraction, and was thus given additional oxytocin IV; IV=intravenous

53

Table 12. No women who received a starting dose of 60 mcg or lower achieved tetanic uterine contraction without additional uterotonics220

Initial dose (mcg)Number of women

starting at each doseNumber of women achieving

tetanic contraction

10 2 0

20 2 0

30 2 0

40 2 0

50 3 0

60 1 0

100 6 5

Table 13. Few adverse events were reported220

Event Number of women, n (%)

Substernal chest pain 1 (5.5)

Hypotension 1 (5.5)

Paresthesia 2 (11.1)

3.5.4.2 Dose-finding study: van Dongen et al. 1998218

This dose-finding study in 45 pregnant women at low risk of PPH and who had normal vaginal deliveries was designed to determine the maximum tolerated dose (MTD) of carbetocin, defined as the dose that would produce dose-limiting adverse events (DLAEs). The DLAEs were characterised as any one or more of the following:

• Drug-related hypotension or hypertension (diastolic blood pressure ≥120 mmHg)

• Vomiting accompanied by severe abdominal pain or headache

• Severe abdominal pain with either a heart rate ≥150 beats per minute or tremors

• Retained placenta

The study design used a form of the continual reassessment method. An initial group of three women received 15 mcg of carbetocin as an IM injection immediately after delivery, and the tolerability in terms of DLAEs was assessed. The data were entered into a statistical model that returned the dose to be administered to the next group of women.

Seven women presented with serious adverse events, of which four included a DLAE (Table 14). All DLAEs were in the 200 mcg dose group and included the following (Table 14):

• Two cases of hypovolaemic shock-induced hypotension following a retained placenta

• One case of PPH-induced hypotension not associated with retained placenta

• One case of retained placenta

n=number of women

54

Table 14. Maximum-tolerated dose for carbetocin was estimated to be 200 mcg, based on serious adverse events, dose-limiting adverse events and interventions218

Number of women

Serious adverse events

Dose (mcg)

Number of women Events Interventions DLAE

15 3 – – – –

30 3 – – – –

50 3 1 AtonyBlood loss ≥1000 mL

Blood transfusion –

70 3 1 Vaginal tearBlood loss ≥1000 mL

Blood transfusionAdditional oxytocics

–

100 6 – – – –

125 3 – – – –

150 3 – – – –

175 3 – – – –

200 18 5 Atony (1)†

Hypovolemic shock (3)†

Retained placenta (4)†

Blood loss ≥1000 mL (4)†

Additional oxytocics (4)†

Blood transfusion (3)†

Manual removal of the placenta (4)†

4

Table 15. Highest blood loss was seen at the lowest and highest carbetocin doses tested218

Carbetocin dose (mcg) Number of women

Total blood loss (mL)

Mean Standard deviation Range

15–50 9 599 459 160–1600

70–125 12 378 364 75–2000

150–175 6 395 191 150–590

200 18 825 782 130–3000

All 45 603 593 75–3000

Based on these data, the MTD for carbetocin was estimated to be 200 mcg. However, there was evidence to suggest that 200 mcg is not the optimal dose: four women had a retained placenta and four of the six women who reported a blood loss of ≥1000 mL were in the 200 mcg group. The highest mean blood loss was found to be at the lowest and highest doses tested (Table 15), with the lowest values found in the range of 70–150 mcg. As the authors reported that the first DLAEs appeared at 125 mcg (not recorded as a DLAE due to a protocol violation), they recommended an optimal dose of 100 mcg for future research.

†Number of women who experienced the adverse event (more than one adverse event could be experienced by women); DLAE=dose-limiting adverse event

55

KEY POINTS Carbetocin is a long-acting, structural analogue of the

naturally-occurring human hormone, oxytocin150

Carbetocin has a similar efficacy and safety profile as oxytocin,45,62–65 and also brings additional benefits:

– Significantly reduces the need for uterotonic interventions (in caesarean sections) and uterine massage (in caesarean and vaginal deliveries)62

– Significantly increases the time before further uterotonics63

– Higher incidence of blood loss ≤500 mL64

– Room temperature-stable formulation is available in a convenient vial presentation,61 which avoids the necessity for cold chain storage

– No need for prolonged IV infusion and subsequent regular monitoring of patients46–48

Carbetocin is much less potent than oxytocin at the human V2 receptor in vitro (EC50: 170 vs 7nM)214 and to date no cases of carbetocin-induced hyponatraemia have been published. Despite this, the risk of water intoxication cannot be completely excluded, particularly in patients also receiving large volumes of intravenous fluids74

Uterine activity after IV administration of carbetocin occurs within 1–2 minutes and lasts approximately 1 hour55

100 mcg of carbetocin administered IV over 1 minute is the recommended optimal dose for maintaining adequate uterine contraction that prevents uterine atony and excessive bleeding61

Absolute bioavailability of carbetocin after IM injection is 76 and 83% for the 0.4 and 0.8 mg doses, respectively,58 which is comparable to the absolute bioavailability of 77% observed for room temperature-stable carbetocin administered IM219

Uterine activity after IM administration lasts significantly longer than IV administration, occurring within 2 minutes and lasting approximately 2 hours55

56

4.1 CLINICAL EFFICACY AND SAFETY OF CARBETOCIN

4.1.1 Overview of the clinical studiesA total of 14 randomised clinical trials comparing carbetocin either to placebo or to other conventional uterotonics have been published to date (Tables 16 and 17).45,63–65,221–230 Of these, 10 trials covering 2635 women in total have been analysed in the Su et al. Cochrane review conducted in 2012, which compared carbetocin with placebo, oxytocin and syntometrine for the prevention of primary PPH.62 The remaining four randomised, controlled, trials were published after the Su et al. 2012 Cochrane analysis was released, including the first study to compare carbetocin with misoprostol plus oxytocin infusion.223,224,229,230

Most trials (8 out of 14) were restricted to mothers delivering by caesarean section,45,63–65,221,223,229,230 but five studies were undertaken in women with vaginal deliveries222,225–228 and one trial included both types of deliveries.224 PPH remains a risk for women after a normal vaginal delivery, as well as following a caesarean section.86,231 Carbetocin is also approved for the vaginal delivery indication in several countries, including to date Russia, Mexico, Kazakhstan, Cuba, Ecuador, El Salvador and Honduras.72–74

Table 16. Trial designs for all 14 studies comparing carbetocin with other uterotonic agents for the prevention of postpartum haemorrhage in women undergoing caesarean or vaginal delivery


Carbetocin versus placebo

Barton et al (1996)221

Double-blind, randomised, trial

• Aged 18–40 years• Women undergoing elective

caesarean section• Singleton pregnancy

• History of:– Congestive heart failure, myocardial

infarction or any other clinically-significant heart disease

– Hypertension requiring treatment within the last two years

– Liver, renal or endocrine disease, including gestational diabetes when treated with insulin

– Known hereditary or acquired coagulopathy (e.g. von Willebrand’s disease or due to medication)

• Placenta praevia or placental abruption• Use of general anaesthesia

CHAPTER IV

57

Table 16. continued


Carbetocin versus oxytocin

Boucher et al (1998)45

Double-blind, randomised, prospective trial

• Aged ≥18 years• Non-labouring• Singleton pregnancy• Normal placental location• Scheduled for elective caesarean

under epidural anaesthesia

• History of:– Heart disease– Hypertension– Cardiac arrhythmia

• Evidence of liver, renal or endocrine disease

Dansereau et al (1999)63

Multi-centre,double-blind, randomised trial

• Scheduled for elective caesarean section through a lower-segment transverse incision under regional anaesthesia

• History of significant disease, including:– Heart disease– Chronic hypertension requiring treatment– Liver– Renal– Endocrine (other than gestational diabetes)

• Known coagulopathy• Placenta praevia or placental abruption• Use of general anaesthesia• Classic uterine incision during caesarean


Double-blind, double-dummy, prospective, randomised trial

• Women with at least one risk factor for PPH, including:– History of PPH or retained placenta– Grand multiparity – Uterine overdistension related to

multiple gestation– Fetal macrosomia– Polyhydramnios– Chorioamnionitis– Antepartum haemorrhage– Induction of labour with oxytocin– Prolonged labour– Rapid–excessive labour

• Aged <18 years• Known or suspected coagulopathy• History of:

– Heart disease– Cardiac arrhythmia– Chronic liver disease– Renal disease– Endocrine disease

• Hypersensitivity to carbetocin or oxytocin

Borruto et al (2009)64

Randomised, prospective, controlled trial

• Women undergoing elective or emergency caesarean section

• At least one risk factor for PPH• Singleton pregnancy (>36 weeks)

• Toxaemia• Eclampsia• Epilepsy

Attilakos et al (2010)65

Double-blind, prospective, randomised trial

• Women undergoing elective or emergency caesarean section

• Term pregnancy (>37 weeks)

• Multiple gestation• Placenta praevia or placental abruption• General anaesthesia• Emergency caesarean section for fetal or

maternal distress where it was not possible or appropriate to recruit or randomise due to time constraints

58

Table 16. continued


Carbetocin versus oxytocin continued

Reyes et al (2011)224

Double-blind, double-dummy, prospective, randomisedtrial

• Women with severe pre-eclampsia• Singleton pregnancy (>28 weeks)

• HELLP syndrome• Blood dyscrasia• Multiple pregnancy

Moertl et al (2011)223


• Women undergoing elective caesarean section under regional anaesthesia

• Term pregnancy

• Placenta praevia or placental abruption• Multiple gestation• Pregnancy-related complications and

disorders including:– Pre-eclampsia– Gestational diabetes– Pre-existing diseases, including

Cardiovascular Renal Hypothyroidism or hyperthyroidism Insulin-dependent diabetes

– Medications known to impact the cardiovascular system

• General anaesthesia

Rosseland et al (2013)230

Double-blind, double-dummy,parallel-group, randomisedtrial

• Women undergoing scheduled caesarean section

• Aged ≥18 years• Singleton pregnancy (≥36 weeks)

• Pre-eclampsia• Placenta praevia• Placenta accreta• von Willebrand disease or other bleeding

disorder• Preoperative systolic arterial pressure

<90 mmHg

Carbetocin versus syntometrine

Leung et al (2006)225


• Women undergoing vaginal delivery• Singleton pregnancy• >34 weeks gestation

• Contraindications for syntometrine or carbetocin, including:– Pre-existing hypertension– Pre-eclampsia– Asthma– History of:

Cardiac disease Renal disease Liver disease

• Risk factors for PPH, including:– Grand multiparity– Uterine fibroids– Prophylactic oxytocin infusion after delivery

59

Table 16. continued


Carbetocin versus syntometrine continued

Nirmala et al (2009)226

Prospective, randomised trial

• Women undergoing vaginal delivery • Term pregnancy • >36 weeks gestation with a viable

fetus • Women with at least one risk factor

for PPH:– History of blood transfusion – Iron sucrose injection pre- or

post-delivery – History of retained placenta – Grand multiparity (parity >5)– Twin pregnancy– Fetal macrosomia (fundal height ≥40 cm or clinical ultrasound estimated fetal weight 3.8–4.0 kg)

– Polyhydramnios (more than one amniotic fluid pocket ≥8 cm or AFI ≥25 cm)

– Induction or augmentation of labour with oxytocin for at least 4 hours

– Prolonged labour (active phase >12 hours)

• Aged <18 years• History or evidence of:

– Liver disease – Renal disease– Vascular disease– Endocrine disease (excluding gestational

diabetes)– Hypersensitivity to carbetocin or oxytocin – Heart disease and hypertension requiring

treatment

Su et al (2009)227


• Women undergoing vaginal delivery• ≥34 weeks gestation

• Elective caesarean section• Risk factors for PPH, including:

– Multiple pregnancy– History of PPH – History of suspected coagulopathy

• Contraindications for study medications, including history of: – Coronary artery disease – Hypertension– Hypersensitivity to carbetocin or

syntometrine

60

Table 16. continued


Carbetocin versus syntometrine continued

Askar et al (2011)228

Double-blind, prospective, randomised controlled trial

• Women undergoing normal vaginal delivery

• Singleton pregnancy • ≥37 weeks gestation

• Aged <18 years• Known or suspected coagulopathy• Contraindications for study medications,

including history of: – Hypertension – Pre-eclampsia– Asthma – Cardiac, renal or liver diseases– Epilepsy– Hypersensitivity to carbetocin or

syntometrine• Women with high risk factors for primary

PPH:– Grand multiparity (parity >5)– Uterine fibroids – Polyhydramnios– Twin pregnancy – Fetal macrosomia– Severe anaemia

• Women with cervical tears who required prophylactic oxytocin after delivery

Carbetocin versus misoprostol + oxytocin

Elgafor el Sharkwy (2013)229

Double-blind, double-dummy, prospective, randomised controlled study

• Fetal macrosomia • Polyhydramnios• Low insertion of the placenta • Multiple gestation • Prolonged labour • Chorioamnionitis• Past history of PPH• Diabetes • High parity (5 previous deliveries)

• Suspected coagulopathy • History of:

– Coronary artery disease – Hypertension – Hypersensitivity to carbetocin – General anaesthesia

• PPH due to causes other than uterine atony

AFI=amniotic fluid index; HELLP=Haemolysis, Elevated Liver enzymes, Low Platelet count; PPH=postpartum haemorrhage

61

Table 17. Dosing protocols and outcomes for all 14 trials comparing carbetocin with other uterotonic agents for the prevention of postpartum haemorrhage in women undergoing caesarean or vaginal deliveries

Trial Delivery

Carbetocin group ComparatorTime of

administration Outcomes†Women Dose WomenMedication,

dose

Carbetocin versus placebo

Barton et al (1996)221

Caesarean section

62 100 mcg IV bolus

57 Saline IV bolus

Immediately after delivery

• Need for additional uterotonics

• Time to uterine contraction

• Time to additional uterotonics

• Uterine tone• Fundal position• Lochia• Vital signs• Adverse events

Carbetocin versus oxytocin


Caesarean section

29 100 mcg IV bolus

28 Oxytocin, 2.5 IU IV bolus + 30 IU IV infusion

Immediately after placental removal

• Volume of intraoperative blood loss


• Uterine tone• Fundal position• Amount and type of lochia • Vital signs

Dansereau et al (1999)63

Caesarean section

329 100 mcg IV bolus

330 Oxytocin 5 IU IV bolus + 20 IU IV infusion

Immediately after infant delivery (87%) or placental removal (13%)

• Need for additional uterotonics within 48 hours

• Fundal position • Uterine tone• Amount of lochia• Vital signs • Drop in haemoglobin

level by Day 2 • Side effects• Onset of adequate

uterine contraction• Time to additional

uterotonics• Postoperative blood

chemistry


Vaginal delivery

83 100 mcg IM bolus

77 Oxytocin 10 IU IV infusion



• Need for uterine massage• Change in haemoglobin• Change in haematocrit• Estimated blood loss• Time to additional

uterotonics• Uterine tone• Amount of lochia• Vital signs • Adverse events

62

Table 17. continued

Trial Delivery



dose


Borruto et al (2009)64

Caesarean section

52 100 mcg IV bolus




• Need for uterine massage• Mean blood loss• Blood loss ≤500 mL• Fundal position• Fundal tone• Uterine tone• Type and amount of lochia• Haematology• Vital signs • Adverse events

Attilakos et al (2010)65

Caesarean section

188 100 mcg IV bolus‡

189 Oxytocin 5 IU IV bolus‡

Immediately after infant delivery


• Estimated blood loss• Postoperative

haemoglobin• Vital signs • Uterine tone• Incidence of blood

transfusion• Adverse effects

Reyes et al (2011)224§

Caesarean section, vaginal delivery

26 100 mcg IV bolus¶



• PPH requiring additional uterotonics

• Post-natal haemoglobin concentration

• Oliguria (<0.5 mL/kg/hour)• Haemodynamic status

(mean arterial pressure and heart rate)

Moertl et al (2011)223§

Caesarean section

28 100 mcg IV bolus

28 Oxytocin 5 IU IV bolus


• Change in maternal heart rate

• Blood pressure• Stroke volume• Cardiac output• Total peripheral resistance• Pre- and post-operative

haemoglobin• Uterine tone• Incidence of other

adverse effects

63

Table 17. continued

Trial Delivery



dose


Rosseland et al (2013)230§

Caesarean section


26 Oxytocin 10 IU IV bolus‡

On delivery of head and shoulders of infant

• Systolic arterial pressure within 5 minutes after intervention

• Uterine contraction score• Estimated blood loss• Decrease in haemoglobin• Time to rescue drug• Side effects• Haemodynamic variables

(mean arterial pressure, diastolic arterial pressure and heart rate)

Carbetocin versus syntometrine

Leung et al (2006)225

Vaginal delivery

150 100 mcg IM bolus

150 Syntometrine (5 IU oxytocin + 0.5 mg ergometrine) IM bolus

On delivery of anterior shoulder of infant

• Haemoglobin at 48 hours postpartum

• Visually estimated intrapartum blood loss

• Incidence of primary PPH (>500 mL)

• Need for blood transfusion

Nirmala et al (2009)226

Vaginal delivery

60 100 mcg IM bolus

60 Syntometrine (5 IU oxytocin + 0.5 mg ergometrine)IM bolus


• Incidence of PPH • Addition of another

oxytocic agent • Haemoglobin drop after

24 hours• Amount of intrapartum

blood loss • Vital signs • Uterine fundal position • Amount of lochia • Adverse events

Su et al (2009)227

Vaginal delivery




• PPH requiring additional uterotonics

• Incidence of PPH (≥500 mL)

• Incidence of severe PPH (≥1000 mL)

• Adverse events

Askar et al (2011)228

Vaginal delivery




• PPH requiring additional uterotonic therapy

• Incidences of PPH (≥500 mL) and severe PPH (≥1000 mL)

• Adverse effects

64

†Outcomes in bold are primary outcomes; ‡administered over 30–60 seconds; §not included in the Su et al. 2012 Cochrane review; ¶administered over 2 minutes; IM=intramuscular; IV=intravenous; PPH=postpartum haemorrhage

4.1.1.1 Carbetocin versus placeboOne Phase III randomised, controlled trial has been conducted, which compared a single 100 mcg IV dose of carbetocin with placebo in women undergoing elective caesarean section (Table 17). The study was reported in the Su et al. 2012 Cochrane review as Barton et al. 1996,62 and showed that treatment with carbetocin significantly reduced the need for additional uterotonic intervention, compared with placebo (13 vs 72%; p=0.001).221 However, nausea and flushing were significantly more common in the carbetocin group than in the placebo group.221 Additionally, carbetocin was associated with a slight decrease in diastolic blood pressure compared with placebo.221

4.1.1.2 Carbetocin versus oxytocinThere are eight clinical trials comparing carbetocin to oxytocin for the prevention of primary PPH so far (Table 17), of which five were included in the Su et al. 2012 Cochrane review.62 In all these studies, carbetocin was given at a dose of 100 mcg and all used IV administration, except the Boucher et al. 2004 study which evaluated carbetocin administered by IM injection,222 whereas the dose of oxytocin varied across all trials.

The authors of the Su et al. 2012 Cochrane review reported that, among women undergoing caesarean section, carbetocin was associated with a significantly reduced need for both additional uterotonics and uterine massage (Figure 10). The difference in uterine massage was also seen in trials of women delivering vaginally. However, there was no significant difference in PPH or severe PPH as defined by blood loss (≥500 mL and ≥1000 mL, respectively).62

Table 17. continued

Trial Delivery



dose

Carbetocin versus misoprostol + oxytocin

Elgafor el Sharkwy (2013)229

Caesarean section


190 Sublingual misoprostol 400 mcg + 20 IU oxytocin IV infusion


• Requirement of additional pharmacological uterotonic

• Difference between pre- and post-operative haemoglobin

• Estimated blood loss• Incidence of blood

transfusion • Adverse events

65

Severe PPH

Any PPH

RR 0.91 (95% CI: 0.39, 2.15)

RR 0.66 (95% CI: 0.46,1.06)RR 0.95 (95% CI: 0.43, 2.09)

CSVD

RR 0.62 (95% CI: 0.44, 0.88)RR 0.93 (95% CI: 0.44, 1.94)

CSVD

RR 0.54 (95% CI: 0.37, 0.79)RR 0.70 (95% CI: 0.51, 0.94)

CSVD

Additionaluterotonics

Uterinemassage

0.0 1.0

Carbetocin better Oxytocin better

2.0 3.0

Figure 10. As compared with oxytocin, carbetocin was associated with a significant reduction in the use of additional uterotonics (caesarean deliveries) and uterine massage (vaginal and caesarean deliveries)62

The clinical trial by Borruto et al. in 2009 showed that more women receiving carbetocin experienced a blood loss of ≤500 mL, compared with those receiving oxytocin (81 vs 55%; p=0.05).64 In addition, the Boucher et al. 1998 study reported that carbetocin was associated with an increased likelihood of bleeding ≤200 mL, compared with oxytocin.45 However, the Su et al. 2012 Cochrane review did not show a difference in levels of blood loss or rates of PPH of ≥500 mL or ≥1000 mL between treatment groups when considering the six available trials.62

In the Su et al. 2012 Cochrane review, a meta-analysis was carried out on adverse events where direct comparisons were made between the two groups. No significant differences between carbetocin and oxytocin were found for any of the analysed adverse events, including nausea and vomiting, where data were available for all pooled trials.62

Subsequent to the Su et al. 2012 Cochrane review, three randomised trials have been published comparing carbetocin to oxytocin. The primary focus in the Moertl et al. 2011 trial was to examine the haemodynamic properties of the two medications. The authors concluded that both agents had comparable effects on blood pressure and heart rate, and were associated with a minor hypotensive effect and an increased heartbeat followed by a minor rebound bradycardia effect.223 These findings were largely confirmed in a study by Rosseland et al. in 2013, which showed that carbetocin and oxytocin had comparable haemodynamic effects, including decreased mean systolic arterial pressure and systemic vascular resistance, and increased cardiac output.230 However, heart rate elevation with carbetocin lasted slightly longer than with oxytocin, which, the authors considered, might be of clinical interest when treating pregnant women who have an increased risk of cardiac events.230

The Reyes et al. 2011 study was conducted in women with severe pre-eclampsia and found that both carbetocin and oxytocin were equally effective at preventing PPH in this population, as measured by haemoglobin levels and the need for additional uterotonics.224 All trials reported no significant differences in the type and frequency of adverse events between carbetocin and oxytocin (see Section 4.3).

CI=confidence interval; CS=Caesarean section; PPH=postpartum haemorrhage; RR=relative risk; VD=vaginal delivery

66

Moreover, data from a prospective, controlled, clinical trial (N=110) conducted by De Bonis et al. in 2012 has suggested that a single IV bolus of 100 mcg carbetocin administered to women undergoing caesarean section under local anaesthesia was associated with significantly lower levels of perceived post-operative pain, compared with a single IV bolus of 10 IU oxytocin followed by 20 IU infused over 24 hours.66

4.1.1.3 Carbetocin versus syntometrineThere are four randomised trials comparing carbetocin with syntometrine, all of which were analysed in the Su et al. 2012 Cochrane review. The pooled data showed no difference between the two medications in the outcomes of PPH (blood loss >500 mL), severe PPH (blood loss >1000 mL) or need for additional uterotonics (Figure 11).62

SeverePPH

AnyPPH

Additionaluterotonics

0.0 1.0

Carbetocin better Syntometrine better

2.0 3.0

RR 0.50 (95% CI: 0.09, 2.72)

RR 1.00 (95% CI: 0.48, 2.07)

RR 0.83 (95% CI: 0.60, 1.15)

Figure 11. Carbetocin and syntometrine showed comparable efficacy62

CI=confidence interval; PPH=postpartum haemorrhage; RR=relative risk

However, the analysis showed that the mean volume of blood lost was significantly lower with carbetocin than with syntometrine across the four randomised studies (mean difference –48.84 mL [95% CI: –94.82, –2.85; p=0.037].

Nausea, vomiting, tremor, sweating and uterine/abdominal pain were all less likely to occur among women given carbetocin than those administered syntometrine (Figure 12). The risk of hypertension (defined as blood pressure ≥140/90 mmHg) was also significantly reduced in women treated with carbetocin at 30 and 60 minutes postpartum.62

67

Nausea RR 0.24 (95% CI: 0.15, 0.40)

Vomiting RR 0.21 (95% CI: 0.11, 0.39)

Tremor RR 0.42 (95% CI: 0.22, 0.83)

Sweating RR 0.33 (95% CI: 0.12, 0.90)

Uterine/abdominal pain RR 0.56 (95% CI: 0.35, 0.92)

Postpartum hypertension

30 min RR 0.06 (95% CI: 0.01, 0.44)

60 min RR 0.07 (95% CI: 0.01, 0.54)

0.0 1.0

Carbetocin better Syntometrine better

2.0

Figure 12. Carbetocin was associated with a lower incidence of nausea, vomiting, tremor, sweating and uterine/abdominal pain, compared with syntometrine62

4.1.1.4 Carbetocin versus misoprostol plus oxytocinOnly one trial, conducted by Elgafor el Sharkwy in 2013, has compared carbetocin with misoprostol plus oxytocin. This was published after the Su et al. 2012 Cochrane review and showed equivalent efficacy in terms of need for additional uterotonics, preoperative and postoperative haemoglobin level change, estimated blood loss and incidence of blood transfusion (see Section 4.5.1).229

4.2 EFFICACY AND SAFETY OF CARBETOCIN VERSUS PLACEBO

4.2.1 Barton et al. 1996221

Design

This was a Phase III randomised, parallel-group, double-blind, multicentre clinical trial in 122 pregnant women undergoing elective caesarean section. Immediately after removal of the placenta, women were administered a single IV bolus of 100 mcg carbetocin (n=62) or a single IV bolus of saline (n=57). The primary outcome was the need for additional uterotonics (Table 17). The study was reported in the Su et al. 2012 Cochrane review as Barton et al. 1996.62

CI=confidence interval; RR=relative risk

68

Efficacy

The study showed that significantly more women in the placebo group required additional uterotonic intervention than in the carbetocin group (72 vs 13%; p=0.001) (Figure 13). Using these data, the Su et al. 2012 Cochrane review calculated the relative risk between the carbetocin and placebo groups as 0.18 (95% CI: 0.09, 0.35); p<0.00001.62

The majority of additional uterotonic interventions occurred in the operating room (100% in the carbetocin group and 90% in the placebo group). The mean time to intervention was similar between the carbetocin and oxytocin groups (9.0 vs 13.8 minutes; p=0.727).

The proportion of women with inadequate uterine tone decreased significantly after carbetocin treatment versus placebo treatment at 1 minute (26 vs 68%; p=0.001), 5 minutes (9 vs 59%; p=0.001), 10 minutes (5 vs 38%; p=0.001) and 20 minutes (0 vs 21%; p=0.003) post-administration.

Safety

The overall rates of nausea and flushing were significantly higher in the carbetocin group than in the placebo group (Table 18). Abdominal pain in the operating room was also more common in the carbetocin group versus the placebo group (18 vs 0%; p=0.048). Although there was an apparent increase in the incidence of pruritis in women treated with carbetocin versus those treated with oxytocin (48 vs 31%; p=0.05), the investigators attributed this observation to an increased use of the pain medication, oxycodone-acetominophen. Carbetocin was reportedly associated with a decrease of 5 mmHg in diastolic blood pressure at 1 minute compared with placebo (55.9 vs 60.9 mmHg; p<0.008).221

Carbetocin (100 mcg IV bolus) Placebo (Saline IV bolus)

100

80

60

40

20

0

***

72%

13%

Patie

nts

requ

irin

g ad

ditio

nal

uter

oton

ic in

terv

entio

n (%

)

Figure 13. Significantly fewer women receiving carbetocin required additional uterotonic intervention than women on placebo

***p=0.001 versus placebo; IV=intravenous

69

4.3 EFFICACY AND SAFETY OF CARBETOCIN VERSUS OXYTOCIN

4.3.1 Boucher et al. 199845

Design

This was a prospective, double-blind, randomised, controlled trial in 57 women with singleton pregnancies undergoing elective caesarean section. Immediately after removal of the placenta, women were administered a single IV bolus of 100 mcg carbetocin followed by an IV infusion of saline (n=29) or a single IV bolus of 2.5 IU oxytocin followed by 30 IU IV infused at a rate of 125 mL/hour for up to 16 hours (n=28). The primary outcome was the volume of intraoperative blood lost during the caesarean section (Table 17).

Blood was collected by aspiration from drug administration until abdominal closure. In addition, blood was extracted from all gauzes used during the procedure, and the haemoglobin was measured using colorimetry. The amount of blood contained within the gauzes was calculated using the formula:

Blood loss (dL) =

Total blood loss was estimated by combining the volume of blood aspirated and the calculated volume of blood collected from gauzes.

Table 18. Nausea and flushing were more commonly reported in the carbetocin group than in the placebo group

Adverse events according to MedDRA system organ class, n (%)

Carbetocin(N=62)

Placebo (N=57) p value

Gastrointestinal disordersNauseaVomitingAbdominal painMetallic taste

25 (40.3)13 (20.9)12 (19.4)

1 (1.6)

13 (22.8)5 (8.8)4 (7.0)3 (5.3)

0.0470.0690.0530.345

Musculoskeletal and connective tissue disorders

Back pain 4 (6.5) 2 (3.5) 0.682

Nervous system disordersTremor Headache

9 (14.5)3 (4.8)

10 (17.5)4 (7.0)

0.6290.707

General disordersFeeling of warmthChills

11 (17.7)1 (3.4)

6 (10.5)–

0.276

Skin and subcutaneous tissue disordersSweating 4 (6.5) 0 (0) 0.121

Vascular disordersFlushing 20 (32.2) 5 (8.8) 0.002

MedDRA=Medical Dictionary for Regulatory Activities; n=number of women experiencing an adverse event; N=total number of women in each treatment group

Amount of haemoglobin in gauzes (mg) Haemoglobin concentration before caesarean section (mg/dL)

70

Efficacy

There was no statistically significant difference between the carbetocin and oxytocin groups in terms of mean blood loss (159 vs 188 mL; p=0.30), irrespective of whether or not women had received additional uterotonics. However, significantly more women given carbetocin had a total blood loss less than 200 mL compared with women given oxytocin (79 vs 53%; p=0.041) (Figure 14).

20

15

10

5

0

Num

ber

of w

omen

Carbetocin (100 mcg IV bolus)

Oxytocin (2.5 IU IV bolus + 30 IU IV infusion up to 16 hours)

<100 100–200 200–300 300–400 400–500

Blood loss range (mL)

Figure 14. Total blood loss for women given carbetocin was significantly more likely to be less than 200 mL compared with those treated with oxytocin

IV=intravenous

The fundal position was below the umbilicus in significantly more women treated with carbetocin than in women treated with oxytocin at 0, 2, 3 and 24 hours after the administration of medication (p=0.047, p=0.047, p=0.047 and p=0.038, respectively), indicating improved uterine involution in the carbetocin group (Figure 15).

Three women treated with oxytocin required additional uterotonics, compared with none in the carbetocin group. There was no difference in the amount and type of lochia or the uterine tone between each group.

71

Safety

There were no significant differences in systolic and diastolic blood pressure, heart rate and respiratory rate between the two women groups. Adverse events reported in each group were broadly comparable (Table 19), but the authors did not carry out a statistical analysis. Three women experienced shortness of breath and one woman reported headache in the carbetocin group compared with none in the oxytocin group, while five women receiving oxytocin reported vomiting compared with two women given carbetocin.

Table 19. Adverse events were comparable between carbetocin and oxytocin

Adverse events according to MedDRA system organ class, n (%) Carbetocin (N=29) Oxytocin (N=28)

Gastrointestinal disordersNauseaVomiting

6 (20.7)2 (6.9)

6 (21.4)5 (17.9)

Skin and subcutaneous tissueItching, pruritis 3 (10.3) 3 (10.7)

General disordersPainChills

1 (3.4)1 (3.4)

2 (7.1)–

Respiratory, thoracic and mediastinal disordersShortness of breath 3 (10.3) –

Nervous system disordersDizzinessHeadache

1 (3.4)1 (3.4)

1 (3.6)–

Heart disordersPremature ventricular contractions – 1 (3.6)


100

90

80

70

60

50

40

30

20

10

0

Wom

en in

eac

h gr

oup

(%)


Oxytocin (2.5 IU IV bolus + 30 IU IV infusion up to 16 hours)

RR0 RR0.25 RR0.5 RR1 W0 W1 W2 W3 W4 W5 W6 W24

* * *

*

Location and time (hours)

Figure 15. Significantly more women in the carbetocin group than in the oxytocin group exhibited a fundus below umbilicus at 0, 2, 3 and 24 hours post-treatment

*p<0.05; IV=intravenous; RR=recovery room; W=ward

72

4.3.2 Dansereau et al. 199963

Design

This was a multi-centre, double-blind, randomised, controlled trial in 659 women undergoing elective caesarean section under regional anaesthesia. Women were administered a single IV bolus of 100 mcg carbetocin followed by an IV infusion of saline (n=329) or a single IV bolus of 5 IU oxytocin followed by 20 IU IV infused at a rate of 125 mL/hour over 8 hours (n=330). Medication was given immediately after delivery of the infant (87% of cases) or removal of the placenta (13% of cases). The primary outcome was the need for additional uterotonics within 48 hours after delivery (Table 17).

Efficacy

A total of 24 women split equally between the treatment groups were excluded from the efficacy analysis due to protocol violations. Out of the remaining women, 4.7% of those who received carbetocin required additional uterotonics compared with 10.1% of those who received oxytocin (OR 2.03 [95% CI: 1.1, 2.8]; p<0.05). Significantly more women in the oxytocin group versus the carbetocin group presented with twin gestations (4 vs 1%; p<0.05) and gestational diabetes (8.5 vs 3.3%; p<0.05), and thus a post hoc evaluation of these potential confounders was conducted. Although no statistical significance was reported, the investigators highlighted that women with gestational diabetes were associated with higher rates of oxytocic interventions versus those without diabetes (16.2 vs 6.9%; OR 2.63 [95% CI: 1.04, 6.66]). However, the difference in the use of additional uterotonics in favour of carbetocin remained significant after correcting for this factor.

The median time before intervention was significantly longer for the carbetocin group versus the oxytocin group (2 hours vs 11 minutes; p<0.001). The majority of these instances of additional intervention took place in the operating room during the caesarean procedure itself (Figure 16).

8

7

6

5

4

3

2

1

0

Prop

ortio

n of

wom

en (%

)

Location where additional uterotonics were administeredRecovery room Postpartum wardOperating room

n=3

n=25

n=7

n=2

n=5 n=5


Oxytocin (5 IU IV bolus + 20 IU IV infusion over 8 hours)

Figure 16. Most instances of additional intervention required in the oxytocin group occurred in the operating room

IV=intravenous

Both groups of women achieved an adequate uterine tone 3–4 minutes after uterotonic administration (92–100% of all women) and in the recovery room (98–100% of all women). There were no significant differences in uterine tone, fundal position or lochia between the two groups.

73

Vital signs and post-operative blood chemistry tests did not differ significantly between treatments, except for a higher post-operative platelet count for carbetocin versus oxytocin (mean ± standard deviation [SD]: 5.1 ± 34 vs –1 ± 32 x109/L; p<0.01). However, the authors deemed this difference too small to be clinically relevant.

Safety

Both study groups shared similar rates and types of adverse events (Table 20). There were two cases of PPH in each group, both of which were associated with a risk factor and none of which were considered to be related to drug treatment.

4.3.3 Boucher et al. 2004222

Design

This was a prospective, double-blind, double-dummy, randomised, controlled trial in 160 women undergoing vaginal delivery who had at least one risk factor for PPH. Immediately after delivery of the placenta, women were administered a single IM bolus of 100 mcg over 2 hours (n=77). The primary outcome was the need for additional uterotonics (Table 17). Estimated blood loss was a secondary outcome; however, no details were provided as to how the volume of blood was determined.



Gastrointestinal disordersAbdominal pain NauseaMetallic tasteVomiting

131882030

(39.8)(26.7)(6.1)(9.1)

127972029

(38.4)(29.3)(6.1)(8.8)

Vascular disordersFlushing 86 (26.1) 76 (23.0)

General disordersFeeling of warmth 65 (19.8) 56 (16.9)

Nervous system disordersHeadacheTremor

46 37

(14.0)(11.2)

43 49

(13.0)(14.8)

Musculoskeletal and connective tissue disorders

Back pain 13 (4.0) 16 (4.8)

Skin and subcutaneous tissue disordersSweating 10 (3.0) 10 (3.0)

Other signs 9 (2.7) 8 (2.4)


74

Efficacy

Twelve women from each treatment arm required additional uterotonics, with no significant difference between the groups in terms of mean blood loss. Where additional uterotonic agents were necessary, women required approximately two additional doses, with no significant difference between the two groups (2.2 for the carbetocin group and 1.8 for the oxytocin group). However, significantly more women receiving oxytocin required uterine massage compared with those receiving carbetocin (62 vs 43%; p=0.02) (Figure 17). This difference was also apparent in the composite outcome of the need for uterine massage and/or uterotonic agents (64 vs 45%; p=0.02) (Figure 17). Although the mean time to administration of additional uterotonics was approximately halved in the oxytocin group versus the carbetocin group (0.5 vs 1.1 hours), this difference was not statistically significant.

Mean blood loss was approximately 410 mL in each group, while 10 women (15.6%) in the carbetocin group and 11 women (16.4%) in the oxytocin group presented with blood loss of >500 mL. All haemodynamic parameters were comparable between the two groups, including differences in haemoglobin concentrations and haematocrit.

Fundal position, uterine tone, vital signs and amount of lochia in the 24 hours postpartum were recorded, with no significant difference observed between the study groups.

Safety

Overall, 43 (51.8%) women in the carbetocin group and 42 (54.5%) women in the oxytocin group reported at least one adverse event, with no statistically significant differences between the medications (Table 21).

100

90

80

70

60

50

40

30

20

10

0

Prop

ortio

n of

wom

en (%

)

Carbetocin (100 mcg IM bolus)

Oxytocin (10 IU IV infusion over 2 hours)

Uterine massageand/or additional uterotonics

n=37

n=49

Uterine massage

n=36

n=48

* *

Figure 17. Significantly fewer women in the carbetocin group required uterine massage and/or any uterotonic intervention, compared with women in the oxytocin group

*p=0.02; IM=intramuscular; IV=intravenous; n=number of women requiring uterine massage and/or any uterotonic intervention

75

4.3.4 Borruto et al. 200964

Design

This was a prospective, randomised, controlled trial in 104 women with singleton pregnancies and at least one risk factor for PPH, who were undergoing elective or emergency caesarean section. Following removal of the placenta, women were administered a single IV bolus of 100 mcg carbetocin (n=52) or 10 IU oxytocin given as an IV infusion over 2 hours (n=52). The primary outcome was the need for additional uterotonics (Table 17). A secondary outcome was mean blood loss, which was measured by collecting blood from the time of drug administration until abdominal closure and using colorimetry to determine the volume.

Efficacy

A total of seven women (6.7%) required additional uterotonics, with a mean time of 60 minutes post-administration. Rates of additional uterotonic use were significantly lower in the carbetocin group than in the oxytocin group (3.8 vs 9.6%; OR=1.83 [95% CI: 0.9, 2.6]; p<0.01) (Table 22). Significantly more women on oxytocin than on carbetocin also required uterine massage (57.7 vs 38.4%; p<0.01) (Table 22), although the time to this intervention was approximately 50 minutes for both groups.



General disorders HeadacheChills

2068

(24.1)(7.2)(9.6)

2211

7

(28.6)(14.3)(9.1)

Nervous system disordersDizzinessTremor

127 5

(14.5)(8.4)(6.0)

96 4

(11.7)(7.8)(5.2)

Heart disordersVasodilatation

86

(9.6)(7.2)

115

(14.3)(6.5)

Blood/lymphatic system disorders Leukocytosis

96

(10.8)(7.2)

108

(13.0)(10.4)

Gastrointestinal disordersNauseaAbdominal painVomiting

75 50

(8.4)(6.0)(6.0)(0)

107 06

(13.0)(9.1)(0)(7.8)

Reproductive system and breast disorders 7 (8.4) 5 (6.5)

Skin and subcutaneous tissue disorders Pruritis

00

(0)(0)

54

(6.5)(5.2)


76

There was no significant difference in the mean volume of blood loss between the two groups; however, numerically more women receiving carbetocin experienced a blood loss of ≤500 mL, compared with women receiving oxytocin (81 vs 55%; p=0.05). Uterine tone, quantity and type of lochia were comparable between the two treatments.

At 24 hours postpartum, the fundus was below the umbilicus (indicative of improved uterine involution) in significantly more women in the carbetocin group than those in the oxytocin group (48 vs 36%; p<0.05) (Table 22).

Safety

Vital signs and haematological values were comparable between the two study groups, and both treatments were associated with similar rates of decreased blood pressure, nausea and vomiting (Table 23).

Table 22. Significantly fewer women in the carbetocin group required uterotonic medication or massage, compared with the oxytocin group

Outcomes Carbetocin (N=52) Oxytocin (N=52) p value

Additional uterotonic intervention

Women requiring uterotonic medication, n (%) 2 (3.8) 5 (9.6) <0.01

Women requiring uterotonic massage, n (%) 20 (38.4) 30 (57.7) <0.01

Blood loss

Mean blood loss, mL 370.1 400.5 NS

Blood loss ≤500 mL, n (%) 40 (81) 29 (55) 0.05

Postpartum uterine involution (number of women with fundus below the umbilicus), %

0 h 9 6 NS

2 h 12 10 NS

6 h 24 16 NS

24 h 48 36 <0.05

n=number of women; N=total number of women in each treatment group; NS=not significant

77

4.3.5 Attilakos et al. 201065

Design

This was a prospective, double-blind, randomised, controlled trial in 377 women undergoing elective or emergency caesarean section. After delivery of the infant, women were administered either a single IV bolus of 100 mcg carbetocin (n=188) or a single IV bolus of 5 IU oxytocin (n=189), with both medications delivered slowly over 30–60 seconds. The primary outcome was the need for additional uterotonics (Table 17). A secondary outcome was mean blood loss, which was estimated by visual assessment, counting the number of used swabs and measuring the volume of aspirated blood.


Adverse events according to MedDRA system organ class, n (%) Carbetocin (N=52) Oxytocin (n=52)

Gastrointestinal disordersAbdominal painNausea and vomitingNauseaVomitingMetallic taste

21 (40.3)–

14 (26.9)4 (7.6)3 (5.7)

20 (38.4)20 (38.4)

–––

Vascular disordersFlushingHypotensionFall in blood pressure (causing dizziness,light-headedness, feeling faint)

13 (25.0)11 (21.1)

–

––

12 (23.0)

Blood/lymphatic system disordersAnaemia 12 (23) –

Nervous system disordersHeadacheTremorDizziness

7 (13.4)6 (11.5)2 (3.8)

15 (28.8)––

General disordersHeat sensationPainLoss of appetite

10 (19.2)2 (3.8)

–

––

5 (9.6)

Respiratory, thoracic and mediastinal disordersDyspnoeaChest painDifficulty in breathing

5 (9.6)2 (3.8)

–

––

4 (7.6)

Skin and subcutaneous tissue disordersPruritusSkin rashes

5 (9.6)–

–10 (19.2)

Musculoskeletal and connective tissue disordersBack pain 2 (3.8) –

Heart disordersArrhythmia – 15 (28.8)


78

Table 24. Significantly fewer women in the carbetocin group required additional uterotonics, compared with women in the oxytocin group

OutcomesCarbetocin

(N=188)Oxytocin (N=189)

RR (95% CI) p value

Additional oxytocics, n (%)5–10 IU oxytocinOther oxytocics

63 (33.5)21 (11.2)42 (22.3)

86 (45.5)29 (15.3)57 (30.2)

0.74 (0.57, 0.95)–

0.74 (0.53, 1.04)

0.023†

–0.11†

Oxytocin infusion, n (%) 40 (21.3) 55 (29.1) 0.73 (0.51, 1.04) 0.10†

Indication for additional oxytocics, n (%)PPH prophylaxisPPH treatment

43 (22.9)20 (10.6)

51 (27.0)35 (18.5)

–0.57 (0.35, 0.96)

–0.43†

Estimated blood loss, mLMedian (IQR)Range

500 (400–700)100–9000

500 (400–600)200–1600

––

0.39‡

–

Estimated blood loss >1000 mL, n (%) 9 (4.8; n=186) 9 (4.8) – –

Uterine tone, median (range) 9 (1–10) 9 (1–10) – 0.14‡

Women transfused with blood, n (%) 4 (2.1) 5 (2.6) – >0.99‡

Haemoglobin, g/dLMean (SD) beforeMean (SD) afterMean fall|| (95% CI)

12.0 (1.0)10.4 (1.3; n=183)

1.6 (1.5, 1.8)

12.1 (1.1; n=188)10.4 (1.3; n=185)

1.6 (1.5, 1.8)

–––

0.84§ (0.92)¶

–

Fundal height above umbilicus on Day 1, n (%) 37 (19.7) 32 (16.9) – –

Secondary PPH, n (%) 0 (0) 0 (0) – –

Uterine tone on Day 1, median (range) 9 (5–10) 9 (7–10) – 0.73‡

Efficacy

Two-fifths of the study population underwent emergency caesarean section rather than an elective procedure and more than half were multiparous. Almost one-third of women had at least one risk factor for PPH, and the proportions were similar between the two groups.

Over one third of women required additional oxytocics in this study, with the likelihood being significantly lower in the carbetocin group than in the oxytocin group (33.5 vs 45.5%; RR 0.74 [95% CI: 0.57, 0.95]; p=0.023) (Table 24). Significantly more women in the oxytocin group than those in the carbetocin group needed additional oxytocics for PPH treatment (18.5 vs 10.6%; RR 0.57 [95% CI: 0.35, 0.96]; p=0.043) rather than for PPH prevention (Table 24), suggesting an increased incidence of PPH in the oxytocin group.

†Continuity-corrected chi-square test; ‡two-tailed Mann–Whitney U test; §two-tailed two-sample Student’s t-test; ¶comparison adjusting for ‘pre’ result using analysis of covariance; ||mean change calculated on complete pairs; CI=confidence interval; IQR=interquartile range; n=number of women; PPH=postpartum haemorrhage; RR=relative risk; SD=standard deviation

There was no significant difference between the two groups regarding other efficacy endpoints, such as estimated blood loss, post-operative uterine tone, incidence of severe PPH (blood loss >1000 mL), incidence of blood transfusion, post-operative haemoglobin change, fundal position and uterine tone (Table 24).

79

Safety

Forty-eight women in the study reported at least one adverse event; 22 (11.7%) and 26 (14%) women in the carbetocin and oxytocin groups, respectively. Although no statistical analysis was performed, the authors concluded that the side effect profiles were similar between the two treatment arms (Table 25).



Carbetocin (N=188)

Oxytocin (N=189)

Gastrointestinal disordersNauseaVomitingAbdominal painMetallic taste

10 (5.3)5 (2.7)1 (0.5)1 (0.5)

7 (3.7)8 (4.2)1 (0.5)1 (0.5)

Vascular disordersFlushing 4 (2.2) 3 (1.6)

Nervous system disordersTremorsDizziness Headache

2 (1.1)2 (1.1)1 (0.5)

4 (2.1)3 (1.6)2 (1.1)

Skin and subcutaneous tissue disordersSweating 1 (0.5) 1 (0.5)

Vascular disordersHypotension 3 (1.6) 2 (1.1)

Respiratory, thoracic and mediastinal disordersShortness of breathWheezing Tightness in throat

2 (1.1)1 (0.5)1 (0.5)

3 (1.6)0 (0)0 (0)

Heart disordersST depressionTachycardiaArrhythmia

1 (0.5)2 (1.1)0 (0)

0 (0)0 (0)

1 (0.5)

Eye disordersBlurred vision 0 (0) 1 (0.5)

Musculoskeletal and connective tissue disordersPain in armBackache

0 (0)0 (0)

1 (0.5)1 (0.5)

Women could experience more than one adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n=number of women who experienced an adverse event; N=total number of women in each treatment group

4.3.6 Reyes et al. 2011224

Design

This was a prospective, double-blind, double-dummy, randomised, controlled trial in 55 women with singleton pregnancies and severe pre-eclampsia undergoing either vaginal delivery or caesarean section. Immediately after removal of the placenta, women were administered a single IV bolus of 100 mcg carbetocin delivered over 2 minutes followed by an IV infusion of Ringer’s lactate solution (n=26) or 20 IU oxytocin given by IV infusion at a rate of 125 mL/hour (n=29). The primary outcome was PPH requiring additional uterotonics (Table 17).

80

Table 26. Carbetocin and oxytocin led to similar outcomes in women with pre-eclampsia

OutcomesCarbetocin

(N=26)Oxytocin (N=29) p value

Need for additional uterotonics, n (%) 0 (0) 1 (3.4) 0.50

Need for blood transfusions, n (%) 0 (0) 3 (10.3) 0.13

Need for instrumental curettage of the uterine cavity, n (%) 2 (7.6) 4 (13.8) 0.41

Postpartum haemoglobin level, g/dL, mean (SD) 10.8 (1.7) 11.1 (1.8) 0.56

Haemoglobin difference (admission–postpartum), mean (SD) 1.24 (0.87) 1.41 (1.12) 0.81

Oliguria, n (%) 6 (23.1) 9 (31.0) 0.26

Efficacy

There was no significant difference between the two groups in any of the outcomes assessed, including need for additional uterotonics, haemodynamic status, change in haemoglobin levels and rates of oliguria (Table 26).

Safety

There was no significant difference in the rates of adverse events reported between the two groups (Table 27). Adverse events were only reported if they were not previously present and appeared immediately after the administration of the study medication. Adverse events that persisted for more than 24 hours were deemed by the authors to be unrelated to the medication used and were not recorded.

n=number of women; N=total number of women in each treatment group; SD=standard deviation

MedDRA=Medical Dictionary for Regulatory Activities; n=number of women experiencing adverse event; N=total number of women in each treatment group

Table 27. Adverse events in women with pre-eclampsia were comparable between carbetocin and oxytocin


Carbetocin (N=26)

Oxytocin (N= 29) p value

Nervous system disordersHeadaches

3 (11.5)

0 (0)

0.09

Gastrointestinal disordersNausea and vomiting

1 (3.8)

0 (0)

0.47

General disordersHot sensationMalaiseFever

1 (3.8)1 (3.8)0 (0)

0 (0)0 (0)

1 (3.4)

0.470.470.53

Vascular disordersFacial flushing

1 (3.8)

0 (0)

0.47

Heart disordersPalpitations

0 (0)

1 (3.4)

0.53

Others 1 (3.8) 0 (0) 0.47

81

4.3.7 Moertl et al. 2011223

Design

This was a prospective, double-blind, randomised, controlled trial in 56 women undergoing elective caesarean section under regional anaesthesia. After delivery of the infant, women were administered either a single IV bolus of 100 mcg carbetocin (n=28) or a single IV bolus of 5 IU oxytocin (n=28), with both medications delivered in 10 seconds. The primary outcome was the change in maternal heart rate (Table 17).

Efficacy

There were no significant differences in baseline maternal characteristics or indications for caesarean section between the two groups. Uterine tone after surgery and the difference in haemoglobin levels were comparable between the two groups, and no women required additional uterotonic interventions.

Safety

Carbetocin and oxytocin had a broadly comparable haemodynamic profile across the outcomes tested. Both medications were associated with an increase in heart rate (Figure 18 and Table 28) followed by minor rebound bradycardia effect. The carbetocin effect was numerically smaller and slightly delayed (Table 28).

Table 28. Changes in heart rate and rebound bradycardia were smaller and slightly delayed in women treated with carbetocin compared with women treated with oxytocin

Outcomes Carbetocin (N=28) Oxytocin (N=28)

Change in heart rate, bpm 14.20 ± 2.45 17.98 ± 2.53

Rebound bradycardia, bpm −3.04 ± 1.95 −6.80 ± 1.92

Time to rebound bradycardia, s 270 200

Change in stroke volume, % +4.9–7.4 +10–12

Change in cardiac output, % +17 +26

Change in total peripheral resistance, % -38.52 ± 3.11 -32.00 ± 3.37

Difference in pre- and post-operative haemoglobin, g/dL 1.10 ± 0.99 1.14 ± 0.76

Uterine tone, scale of 1–10 7.65 ± 1.56 7.83 ± 1.70

All data are mean ± standard deviation, where reported; bpm=beats per minute; N=total number of women in each treatment group

Heart rates in women who received carbetocin recovered gradually from peak levels, whereas those who received oxytocin experienced rebound bradycardia of approximately 7% below baseline heart rate levels (Figure 18A). Although these differences were statistically significant, they were not considered to be clinically relevant by the study authors. Furthermore, there was no statistically significant difference between the two treatment arms once the data were adjusted for baseline levels (Figure 18B).

82

115

110

105

100

95

90

85

80

75

Hea

rt r

ate

(bea

ts p

er m

inut

e)

0 50 100

* *† * * * * * * * ** ****

150 200 250

Time after medication (seconds)

300 350 400 450 500

Oxytocin (5 IU IV bolus)


25

20

15

10

5

0

–5

–10

–15

Chan

ges

in h

eart

rat

e(b

eats

per

min

ute)

50 100 150 200 250


300 350 400 450 5000

*

A

B

Figure 18. Changes in maternal heart rate following drug administration were similar between carbetocin and oxytocin after adjustment for baseline levels

*p<0.05; †p<0.001; data are displayed as means ± standard error of means. A: maternal heart rate at different time points after the administration of the study medication. Baseline maternal heart rate (horizontal lines) corresponds to the first measurement (time after medication of 0 seconds). B: changes in maternal heart rate at the same time points, but after adjusting for baseline; IV=intravenous

Both carbetocin and oxytocin showed a hypotensive effect, with mean arterial blood pressure decreasing by 19.38 mmHg and 22.42 mmHg, respectively. The effect was most pronounced at 30–40 seconds post-administration.

Similar to the heart rate profiles of both medications, the recovery of systolic blood pressure, diastolic blood pressure and total peripheral resistance were delayed and of lower magnitude in women receiving carbetocin versus oxytocin (Figures 19A–21A). However, the differences between the two treatment groups were considered to be statistically insignificant following correction for baseline levels (Figures 19B–21B). The authors attributed the slight delay during the recovery phase of all haemodynamic parameters assessed to the longer half-life of carbetocin compared with oxytocin.

83


Carbetocin (100 mcg IV bolus)135130125120115110105100

95908580

Syst

olic

blo

od p

ress

ure

(mm

Hg)

50 100

* * **

150 200 250

Time after study medication (seconds)

300 350 400 450 500

5

0

–5

–10

–15

–20

–25

–30

–35

Chan

ges

in s

ysto

lic

bloo

d pr

essu

re (m

mH

g)

50 100 150 200 250

Time after study medication (seconds)

300 350 400 450 500

0

0

A

B

Figure 19. Changes in maternal systolic blood pressure following drug administration were similar between carbetocin and oxytocin after adjustment for baseline levels

*p<0.05; data are displayed as means ± standard error of means. A: maternal systolic blood pressure at different time points after the administration of the study medication. Baseline maternal systolic blood pressure (horizontal lines) corresponds to the first measurement (time after medication of 0 seconds). B: changes in maternal systolic blood pressure at the same time points, but after adjusting for baseline; IV=intravenous

84

85

80

75

70

65

60

55

50

45

Dia

stol

ic b

lood

pre

ssur

e(m

mH

g)

50 100

** **

150 200 250


300 350 400 450 500



0

–5

–10

–15

–20

–25

Chan

ges

in d

iast

olic

bl

ood

pres

sure

(mm

Hg)

50 100 150 200 250


300 350 400 450 500

A

B

0

0

Figure 20. Changes in maternal diastolic blood pressure following drug administration were similar between carbetocin and oxytocin after adjustment for baseline levels

*p<0.05; data are displayed as means ± standard error of means. A: maternal diastolic blood pressure at different time points after the administration of the study medication. Baseline maternal diastolic blood pressure (horizontal lines) corresponds to the first measurement (time after medication of 0 seconds). B: changes in maternal diastolic blood pressure at the same time points, but after adjusting for baseline; IV=intravenous

85

There were no differences in the adverse events recorded between the two groups (Table 29).

1100

1000

900

800

700

600

500

Tota

l per

iphe

ral r

esis

tanc

e (d

yne•

s/cm

5 )

0 50 100

** **

150 200 250


300 350 400 450 500

Oxytocin (5 IU IV bolus)Carbetocin (100 mcg IV bolus)

50

0

–50

–100

–150

–200

–250

–300

–350

–400

–450

Cha

nges

in to

tal p

erip

hera

lre

sist

ance

(dyn

e•s/

cm5 )

0 50 100 150 200 250


300 350 400 450 500

*** *

A

B

*p<0.05; data are displayed as means ± standard error of means. A: maternal total peripheral resistance at different time points after the administration of the study medication. Baseline maternal total peripheral resistance corresponds to the first measurement (time after medication of 0 seconds). B: changes in maternal total peripheral resistance at the same time points, but after adjusting for baseline; IV=intravenous

Figure 21. Changes in maternal total peripheral resistance following drug administration were similar between carbetocin and oxytocin after adjustment for baseline levels

86



Adverse events 10 (35.7) 11 (39.3)

Gastrointestinal disordersNausea

3 (10.7)

4 (14.3)

Vascular disordersFlushing

4 (14.3)

3 (10.7)

Nervous system disordersHeadache

2 (7.1)

2 (7.1)

Heart disordersTachycardia

0 (0)

1 (3.6)

General disordersFeeling warm

1 (3.6)

0 (0)

Respiratory, thoracic and mediastinal disordersShortness of breath

0 (0)

1 (3.6)


4.3.8 Rosseland et al. 2013230

Design

This was a randomised, double-blinded, placebo-controlled, parallel-group trial in 76 women with singleton pregnancies undergoing elective caesarean delivery. After delivery of the head and shoulders of the infant, women were administered a single IV bolus of 100 mcg carbetocin (n=26), a single IV bolus of 10 IU oxytocin (n=25) or a single IV bolus of saline (n=25). The study medication was delivered slowly over 60 seconds. The primary outcome was the difference in systolic arterial pressure (SAP) within 5 minutes after drug administration (Table 17). A secondary outcome was estimated blood loss, which was calculated using the formula:

Calculated estimated blood loss =

(0.75 x [height in inches] x 50) + ([weight in pounds] x 50) x

Efficacy

The oxytocin and carbetocin groups exhibited a pronounced decrease in SAP, compared with the placebo group (Figure 22A). However, there was no significant difference in the hypotensive effects between the uterotonic groups, with a reduction in SAP in the carbetocin and oxytocin groups of 19 and 21%, respectively.

(pre-delivery haematocrit – post-delivery haematocrit) (pre-delivery haematocrit)

87

150

140

130

120

110Syst

olic

art

eria

l pre

ssur

e (m

mH

g)

–1 0

↑1 2 3 4

Time (minutes)

5 6 7 8

***

Mea

n ar

teri

al p

ress

ure

(mm

Hg)

75

70

65

60

55

50–1 0

↑1 2 3 4

Time (minutes)

5 6 7 8

Dia

stol

ic a

rter

ial p

ress

ure

(mm

Hg)

110

100

90

80

70–1 0

↑1 2 3 4

Time (minutes)

5 6 7 8

Drugadministration

Drugadministration

Drugadministration


Placebo (Saline IV bolus)

A

C

B

Figure 22. Changes in systolic arterial pressure, mean arterial pressure and diastolic arterial pressure were broadly similar with carbetocin and oxytocin

***p<0.001 carbetocin versus placebo; IV=intravenous

88

Although the onset of hypotension was similar between the two uterotonics, the time to reach trough SAP levels was significantly shorter with carbetocin than with oxytocin (63 vs 80 seconds; p=0.006). The hypotensive effect was nearly eliminated by 150 seconds post-administration for both carbetocin and oxytocin; however, the SAP level for the carbetocin group remained significantly lower than placebo at this time point (Figure 22A). The changes in mean arterial pressure and diastolic arterial pressure closely mirrored those for SAP (Figure 22B and 22C).

The heart rate of women increased in all three groups in the first 90 seconds after drug administration, but was significantly higher in women given carbetocin and oxytocin, compared with those given placebo (Figure 23). By 5 minutes post-administration, the heart rate of women in the oxytocin and placebo groups had reduced to their respective baseline levels. By contrast, the heart rate of women in the carbetocin group had yet to reach baseline levels after 5 minutes.

Drugadministration

100

90

80

70–1 0

↑1 2 3 4

Time (minutes)

5 6 7 8

Hea

rt r

ate

(bea

ts p

er m

inut

e) Oxytocin (10 IU IV bolus)Carbetocin (100 mcg IV bolus)


***

Figure 23. Changes in heart rate were comparable with carbetocin and oxytocin

***p<0.001 baseline versus 5 minutes post-administration in the carbetocin group; bpm=beats per minute; IV=intravenous

Cardiac output increased from baseline levels by 96% in carbetocin-treated women and by 82% in oxytocin-treated women (Figure 24A). The maximum increase in cardiac output was reached after 58 seconds with carbetocin and after 75 seconds with oxytocin.

Similarly, stroke volume increased by approximately 25% over baseline in the two uterotonic groups, which was significantly higher than the increase observed in the placebo group (Figure 24B). By contrast, systemic vascular resistance decreased in women who received either carbetocin or oxytocin, but increased slightly in those who received placebo (Figure 24C).

89

The calculated volume of blood loss was comparable between the carbetocin, oxytocin and placebo groups (579 mL, 841 mL and 853 mL, respectively). Similarly, the decrease in haemoglobin concentration after 2 hours post-administration was similar in women in the carbetocin, oxytocin and placebo groups (–0.50 g/dL, –0.82 g/dL and –0.84 g/dL, respectively).

Uterine contraction was determined to be adequate after administration of carbetocin or oxytocin. Additional uterotonic intervention was required for five women in the carbetocin group and five women in the oxytocin group. By comparison, 23 women in the placebo group required additional oxytocin to achieve adequate uterine contraction. The time to additional uterotonics was numerically lower in the oxytocin group versus the carbetocin group (227 vs 536 seconds), but this difference was not significant.

A

B

C

Drugadministration

80

60

40

20

0

–20–1 0

↑1 2 3 4 5 6 7 8

Card

iac

outp

ut (%

)St

roke

vol

ume

(%)

Syst

emic

vas

cula

rre

sist

ance

(%)

Time (minutes)



30

20

10

0

–10–1 0

↑1 2 3 4 5 6 7 8

20

0

–20

–40

–60–1 0

↑1 2 3 4 5 6 7 8

Figure 24. Changes in cardiac output, stroke volume and systemic vascular resistance were similar between carbetocin and oxytocin

IV=intravenous

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Safety

Significantly more women in the carbetocin (n=9 [36%]) and oxytocin groups (n=9 [34.6%]) reported one or more adverse events, compared with the placebo group (n=2 [8.0%]; p=0.001). However, there was no significant difference in the number and range of adverse eavents reported, the degree of discomfort experienced by women or the median duration of adverse events between the carbetocin and oxytocin groups (Table 30).



Carbetocin (N=25) Oxytocin (N=26) Placebo (N=25)

Gastrointestinal disordersDry mouthMetallic taste

1 (4.0)0 (0)

0 (0)1 (3.8)

0 (0)0 (0)

General disordersFeeling of warmth 2 (8.0) 2 (7.7) 1 (4.0)

Nervous system disordersHeadache 2 (8.0) 3 (11.5) 0 (0)

Vascular disordersFlushing 0 (0) 2 (7.7) 1 (4.0)

Heart disordersPalpitations 0 (0) 3 (11.5) 0 (0)

Respiratory, thoracic and mediastinal disorders Chest painDyspnoeaNasal congestion

2 (8.0)1 (4.0)1 (4.0)

2 (7.7)0 (0)

1 (3.8)

0 (0)0 (0)0 (0)


4.4 EFFICACY AND SAFETY OF CARBETOCIN VERSUS SYNTOMETRINE

4.4.1 Leung et al. 2006225

Design

This was a prospective, double-blind, randomised, controlled trial in 300 women with singleton pregnancies undergoing vaginal delivery. Following delivery of the anterior shoulder of the infant, women were administered either a single IM bolus of 100 mcg carbetocin (n=150) or a single IM bolus of syntometrine (5 IU oxytocin plus 0.5 mg ergometrine) (n=150). The primary outcome was the reduction in haemoglobin level at 48 hours postpartum (Table 17). A secondary outcome was mean blood loss, which was estimated by visual assessment during delivery.

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The mean blood loss and incidence of PPH (>500 mL or >1000 mL) were similar on administration of carbetocin or syntometrine (Table 32). There was one case of massive haemorrhage (>2000 mL) in the syntometrine group, and all cases of PPH occurred within 1 hour of delivery. No other pre-specified secondary outcome approached statistical significance (Table 32).

Table 32. Volume of blood loss and incidence of postpartum haemorrhage were similar between carbetocin and syntometrine

OutcomesCarbetocin

(N=150)Syntometrine

(N=150)Mean

difference RR 95% CI

Mean blood loss, mL† 232 ± 122 249 ± 175 –17 – –51, 18

Primary postpartum haemorrhage, n (%)Blood loss ≥500 mLBlood loss ≥1000 mL

6 (4)6 (4)0 (0)

3 (2)2 (1.3)1 (0.7)

–––

2.003.00

–

0.50, 8.320.61, 15.53

–

Repeat oxytocic injection, n (%) 13 (8.7) 10 (6.7) – 1.30 0.56, 3.13

Need for blood transfusion, n (%) 5 (3.3) 2 (1.3) – 2.50 0.49, 13.36

Manual removal of placenta, n (%) 1 (0.7) 3 (2) – 0.33 0.03, 3.20

Mean duration of third stage, minutes† 11.6 ± 17.4 10.4 ± 4.2 1.2 – –1.7, 4.1

Duration of third stage, n (%)≤10 minutes11–30 minutes>30 minutes

128 (85.3)21 (14)1 (0.7)

126 (84)23 (15.3)

1 (0.7)

–––

1.020.911.00

0.59, 2.080.47, 1.71

0.06, 16.14

†Data are presented as mean ± standard deviation; CI=confidence interval; n=number of women; N=total number of women in each treatment group; RR=relative risk

Table 31. Haemoglobin concentrations before and 48 hours after delivery were similar between carbetocin and syntometrine

OutcomesCarbetocin

(N=150)Syntometrine

(N=150)Mean

difference RR 95% CI

Haemoglobin at onset of labour, g/dl† 11.6 ± 1.1 11.8 ± 1.2 –0.2 – –0.5, 0

Haemoglobin on postpartum day 2, g/dl† 10.2 ± 1.4 10.4 ± 1.5 –0.2 – –0.5, 0.2

Mean fall in haemoglobin, g/dl† 1.4 ± 1.1 1.5 ± 1.3 –0.1 – –0.4, 0.2

Mean drop in haemoglobin concentration, %† 11.6 ± 9.4 12.2 ± 10.3 –0.6 – –2.8, 1.7

Percent drop of haemoglobin, n (%)>20%>10%

24 (16) 75 (50)

33 (22)82 (54)

––

0.720.91

0.3, 1.210.77, 1.90

†Data are presented as mean ± standard deviation; CI=confidence interval; n=number of women; N=total number of women in each treatment group; RR=relative risk

Efficacy

The mean decrease in haemoglobin by 48 hours postpartum was 1.4 g/dL in the carbetocin group and 1.5 g/dL in the syntometrine group, with no statistically significant difference between them (Table 31). Numerically, fewer women in the carbetocin group than in the syntometrine group presented a haemoglobin concentration drop of >10% (50 vs 54%) or >20% (16 vs 22%), but the differences were not statistically significant (Table 32).

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Safety

Compared with syntometrine, carbetocin was associated with significantly lower rates of nausea (7.3 vs 1.3%; RR 0.18 [95% CI: 0.04, 0.78]) and vomiting (6.7 vs 0.7%; RR 0.10 [95% CI: 0.01, 0.74]) (Table 33). The rate of hypertension was also markedly lower with carbetocin versus syntometrine at 30 minutes (0 vs 5.3%; p<0.01) and 60 minutes (0 vs 4%; p<0.05) postpartum. However, tachycardia within 60 minutes of delivery occurred more frequently in the carbetocin group than in the syntometrine group (32 vs 19%; RR 1.68 [95% CI: 1.03, 3.57]) (Table 33).

There was no difference between the two treatment groups regarding the rates of facial flushing, headache, shivering and pain over the injection site.

Table 33. Lower rates of nausea, vomiting and hypertension were reported in the carbetocin group than in the syntometrine group


Carbetocin(N=150)

Syntometrine (N=150)

Mean difference RR 95% CI

Gastrointestinal disorders, n (%)NauseaVomiting

2 (1.3)1 (0.7)

11 (7.3)10 (6.7)

––

0.180.10

0.04, 0.780.01, 0.74

General disorders, n (%)ShiveringPain over injection site

2 (1.3)0 (0)

6 (4)1 (0.7)

––

0.33–

0.06, 1.63–

Nervous system disorders, n (%)Headache

1 (0.7)

2 (1.3)

–

0.50

0.05, 5.54

Vascular disorders, n (%)Facial flushing

0 (0)

3 (2)

–

–

–

Haemodynamic measures

Tachycardia (pulse ≥100 bpm) within 60 minutes post-delivery, n (%) 32 (21.3) 19 (12.7) – 1.68 1.03, 3.57

Mean systolic blood pressure immediately after delivery, mmHg† 113.7 ± 11.6 116.7 ± 12.9 –3.0 – –5.7, –0.2

Mean diastolic blood pressure immediately after delivery, mmHg† 63.4 ± 9.2 67.2 ± 9.4 –3.8 – –6.0, –1.7

Mean systolic blood pressure 30 minutes after delivery, mmHg† 112.9 ± 10.3 118.1 ± 11.6 –5.2 – –7.8, –2.8

Mean diastolic blood pressure 30 minutes after delivery, mmHg† 64.5 ± 8.4 68.1 ± 10.0 –3.6 – –5.7, –1.5

Mean systolic blood pressure 60 minutes after delivery, mmHg† 113.3 ± 10.5 117.1 ± 11.9 –3.8 – –6.4, –1.3

Mean diastolic blood pressure 60 minutes after delivery, mmHg† 64.7 ± 8.7 67.9 ± 8.8 –3.2 – –5.2, –1.2

Hypertension (blood pressure ≥140/90 mmHg), n (%)

Immediately after delivery30 minutes after delivery60 minutes after delivery

2 (1.3)0 (0)0 (0)

4 (2.7)8 (5.3)**

6 (4)*

–––

0.5––

0.09, 2.74––

*p<0.05 by Fisher’s exact test; **p<0.01 by Fisher’s exact test; †data are presented as mean ± standard deviation; bpm=beats per minute; CI=confidence interval; MedDRA=Medical Dictionary for Regulatory Activities; n=number of women experiencing an adverse event; N=total number of women in each treatment group; RR=relative risk

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4.4.2 Nirmala et al. 2009226

Design

This was a prospective, randomised, controlled trial in 120 women with at least one risk factor for PPH and undergoing vaginal delivery. After delivery of the infant, women were administered either a single IM bolus of 100 mcg carbetocin (n=60) or a single IM bolus of syntometrine (5 IU oxytocin plus 0.5 mg ergometrine; n=60). The primary outcome was the incidence of PPH, defined as blood loss of ≥500 mL (Table 17). Blood loss was measured using the gravimetric method, whereby a plastic sheet was placed under the thighs of the woman after delivery of the infant to enable collection of the blood.

Efficacy

Numerically, fewer women in the carbetocin group experienced PPH compared with those in the syntometrine group (5 vs 10%; p>0.05). In support of these data, the mean estimated blood loss was significantly lower in women treated with carbetocin versus syntometrine (244 vs 343 mL; p<0.001) (Table 34).

Table 34. Compared with women treated with syntometrine, the women who received carbetocin showed significantly lower blood loss and a decreased reduction in haemoglobin levels

OutcomesCarbetocin

(N=60) Syntometrine

(N=60) p value

Estimated blood loss (range), mL† 244 ± 114 (78–578)

343 ± 143(89–870) <0.001

Pre-delivery haemoglobin, g/dL† 11.3 ± 1.1 11.4 ± 1.0 NS

Post-delivery haemoglobin, g/dL† 11.0 ± 1.1 11.0 ± 1.0 NS

Haemoglobin difference, g/dL† 0.3 ± 0.2 0.4 ± 0.2 <0.001

Blood loss, n (%)

<100 mL 4 (7) 2 (3) –

100–199 mL 13 (21) 5 (8) –

200–299 mL 27 (45) 15 (25) –

300–399 mL 10 (17) 20 (33) –

400–499 mL 3 (5) 12 (20) –

≥500 mL (PPH) 3 (5) 6 (10) NS

Drop in haemoglobin level, n (%)

<5% 57 (95) 50 (83) –

5–10% 3 (5) 9 (15) –

>10% 0 (0) 1 (2) –

†Data are mean ± standard deviation; n=number of women; N=total number of women in each treatment group; NS=not significant; PPH=postpartum haemorrhage

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Syntometrine was associated with a significant reduction (from pre- to post-delivery) in haemoglobin levels, compared with carbetocin (0.4 vs 0.3 g/dL; p<0.001). Furthermore, a decrease in haemoglobin level of <5% was observed in 95% of women in the carbetocin group versus 83% of women in the syntometrine group. By contrast, no women treated with carbetocin experienced a haemoglobin drop of >10%, compared with one woman who received syntometrine (Table 34).

There were no significant differences between the carbetocin and syntometrine groups in the need for additional oxytocic agents (3 vs 9 women; p>0.05), time to additional uterotonic administration (15 vs 12 minutes; p>0.05) and requirement for blood transfusion (0 vs 1 woman).

Safety

There were no significant differences between the carbetocin and syntometrine groups, in terms of adverse events or complications arising from treatment (Table 35).

Table 35. Adverse events were comparable between carbetocin and syntometrine


Carbetocin(N=60)

Syntometrine(N=60) p value

Gastrointestinal disordersAbdominal painVomitingNauseaMetallic taste

1 (1.7)0 (0)0 (0)0 (0)

3 (5.0)2 (3.3)1 (1.7)0 (0)

NSNSNS–

Vascular disordersFlushing 0 (0) 0 (0) –

Nervous system disordersHeadacheTremors

2 (3.3)0 (0)

1 (1.7)0 (0)

NS–

Musculoskeletal and connective tissue disordersBack pain 0 (0) 1 (1.7) NS

Skin and subcutaneous tissue disordersSweating 0 (0) 0 (0) –

General disordersFeeling warm 0 (0) 0 (0) –

MedDRA=Medical Dictionary for Regulatory Activities; n=number of women who experienced an adverse event; N=total number of women in each treatment group; NS=not significant

4.4.3 Su et al. 2009227

Design

This was a prospective, double-blind, randomised, controlled trial in 370 women with singleton pregnancies undergoing vaginal delivery. Following delivery of the anterior shoulder of the infant, women were administered either a single IM bolus of 100 mcg carbetocin (n=185) or a single IM bolus of syntometrine (5 IU oxytocin plus 0.5 mg ergometrine) (n=185). The primary outcome was PPH requiring additional uterotonics (Table 17). The volume of blood lost during the delivery was visually estimated by the attending midwives and obstetricians.

95

Efficacy

There was no significant difference between the proportion of women in the carbetocin group and the syntometrine group who required additional uterotonics (13.5 vs 16.7%; p=0.38) (Table 36). Subgroup analysis did not reveal any difference in the primary outcome among primiparous and multiparous women (Table 36). The mean estimated blood loss was also similar between carbetocin and syntometrine (217.4 vs 223.1 mL; p=0.29).

The rates of PPH at ≥500 mL were identical between the two groups (1.6% for both treatment arms) and there was no difference in the need for blood transfusion (Table 36). One woman presented with severe PPH (≥1000 mL) in the syntometrine group, compared with none in the carbetocin group.

Safety

Syntometrine versus carbetocin was associated with significantly higher rates of nausea (24.9 vs 5.9%; RR 4.2 [95% CI: 2.2, 7.8]; p<0.001) and vomiting (16.2 vs 3.8%; RR 4.3 [95% CI: 1.9, 9.5]; p<0.001) (Table 37). Furthermore, the severity of nausea and vomiting associated with syntometrine was likely to be moderate to very severe (Table 37).

Table 36. Need for additional uterotonics and the mean blood loss were comparable between carbetocin and syntometrine women

OutcomesCarbetocin

(N=185)Syntometrine

(N=185) p value Total

(N=370)

Need for additional uterotonics, n (%)PrimiparousMultiparous

25 (13.5)11 (15.1)13 (13.4)

31 (16.8)12 (16.4)16 (16.7)

0.380.810.53

56 (15.1)23 (15.8)29 (15.0)

PPH (≥500 mL), n (%) 3 (1.6) 3 (1.6) 1.00 6 (1.6)

Severe PPH (≥1000 mL), n (%) 1 (0.5) 0 (0.0) 1.00 1 (0.3)

Need for blood transfusion, n (%) 1 (0.5) 0 (0.0) 1.00 1 (0.3)

Mean blood loss, mLMean (SD)RangeMedian

217.4 (99.2)50–1250

200

223.1 (76.3)100–700

200

0.29 220.2 (88.4)50–1250

200

Length of hospital stay, daysMean (SD)Median

1.82 (0.60)2.00

1.81 (0.76)2.00

0.94 1.81 (0.76)

n=number of women; N=total number of women in each treatment group; PPH=postpartum haemorrhage; SD=standard deviation

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Table 37. Rates of nausea and vomiting were significantly elevated in the syntometrine group compared with the carbetocin group


Carbetocin (N=185)

Syntometrine (N=185)

p value

RR (95% CI)

Nervous system disordersDizziness HeadacheTremor

21 (11.4)15 (8.1)11 (5.9)

28 (15.1)18 (9.7)

26 (14.1)

0.280.580.01

––

2.4 (1.2, 4.7)

Reproductive system and breast disorders Uterine pain

21 (11.4)

37 (20.0)

0.002

7.0 (1.6, 30.3)

Skin and subcutaneous tissue disorders PruritusSweating

16 (8.6)5 (2.7)

12 (6.5)15 (8.1)

0.430.02

–3.0 (1.1, 8.1)

Gastrointestinal disordersNausea

Moderate to very severeVomiting

Moderate to very severeRetching

11 (5.9)2 (1.1)7 (3.8)1 (0.5) 2 (1.1)

46 (24.9)25 (13.5)30 (16.2)18 (9.7)14 (7.6)

<0.001<0.001<0.001<0.0010.002

4.2 (2.2, 7.8)12.5 (3.0, 52.6)

4.3 (1.9, 9.5)17.8 (2.4, 142.8)

7.0 (1.6, 30.3)

General disorders Warmth

11 (5.9)

14 (7.6)

0.53

–

Psychiatric disorders Anxiety

9 (4.9)

10 (5.4)

0.82

–


7 (3.8)

10 (5.4)

0.46

–

Respiratory, thoracic and mediastinal disorders Chest painDyspnoea

6 (3.2)5 (2.7)

3 (1.6)6 (3.2)

0.340.77

––

CI=confidence interval; MedDRA=Medical Dictionary for Regulatory Activities; n=number of women experiencing an adverse event; N=total number of women in each treatment group; RR=relative risk

Women in the syntometrine group were significantly more likely to experience tremor, sweating, retching and uterine pain, compared with those in the carbetocin group (Table 37). Despite the severity of some adverse events associated with the oxytocin/ergometrine combination, the mean length of hospitalisation was similar in the carbetocin and syntometrine groups (1.82 vs 1.81 days; p=0.936).

4.4.4 Askar et al. 2011228

Design

This was a prospective, double-blind, randomised, controlled trial in 240 women with singleton pregnancies undergoing vaginal delivery. Following delivery of the anterior shoulder of the infant, women were administered either a single IM bolus of 100 mcg carbetocin (n=120) or a single IM bolus of syntometrine (5 IU oxytocin plus 0.5 mg ergometrine) (n=120). The primary outcome was PPH requiring additional uterotonics (Table 17). Blood loss was measured by the gravimetric method using a plastic sheet, which was placed under the thighs of the woman after delivery of the infant.

97

The estimated mean blood loss was significantly lower in the carbetocin group compared with the syntometrine group (224.6 vs 306.1 mL; p<0.0001) (Table 38). The mean drop in haemoglobin concentration 24 hours after delivery was also significantly reduced in the carbetocin group compared with the syntometrine group (0.8 vs 1.1 g/dL; p<0.01) (Table 38).

Safety

Women in the carbetocin group were significantly less likely to experience nausea than those in the syntometrine group (3.3 vs 10.4%; p<0.05), as well as vomiting (2.5 vs 10%; p<0.05) (Table 39). The rate of hypertension was also significantly lower in the carbetocin group versus the syntometrine group at 30 minutes (0.0 vs 6.7%; p<0.01) and 60 minutes (0.0 vs 5.8%; p<0.05) postpartum. The incidence of facial flushing, headache and abdominal pain were low and similar in both groups.

Table 38. Women treated with carbetocin had a significantly lower mean blood loss and a reduced drop in haemoglobin levels compared with those treated with syntometrine

Outcomes

Carbetocin(N=120)

Syntometrine(N=120)

p value

Need for additional uterotonics, n (%) 18 (15.0) 21 (17.5) 0.72

Primiparous 7 (5.8) 9 (7.5) 0.79

Multiparous 11 (9.2) 12 (10.0) 0.99

Primary PPH (≥500 mL), n (%) 2 (1.7) 3 (2.5) 0.99

Severe PPH (≥1000 mL), n (%) 0 (0) 1 (0.8) 0.85

Need for blood transfusion, n (%) 0 (0) 1 (0.8) 0.85

Mean blood loss, mL† 224.6 ± 110.6 306.1 ± 95.7 <0.0001

Haemoglobin at onset of labour, g/dL† 11.5 ± 1.3 11.7 ± 1.2 0.21

Haemoglobin on postpartum day 1 (g/dL) (24 h after delivery)† 10.9 ± 1.1 10.6 ± 1.2 0.04

Haemoglobin difference (g/dL) (mean fall in haemoglobin)† 0.8 ± 0.2 1.1 ± 0.3 <0.0001

Urine output during postpartum day 1 (mL/h)† 48.3 ± 2.7 47.9 ± 2.6 0.24

†Data are mean ± standard deviation; n=number of women; N=total number of women in each treatment group; PPH=postpartum haemorrhage; SD=standard deviation

Efficacy

There was no significant difference between the carbetocin and syntometrine groups, in terms of the need for the use of additional uterotonic agents (15 vs 17.5%; p=0.72) (Table 38). Furthermore, there was no significant difference in the incidence of PPH (≥500 mL) or severe PPH (≥1000 mL) between the two groups (Table 38).

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Table 39. Lower rates of nausea, vomiting and hypertension were reported in the carbetocin group than in the syntometrine group


Carbetocin(N=120)

Syntometrine(N=120)

p value


1 (0.83)

2 (1.66)

0.99

Gastrointestinal disordersNauseaVomitingAbdominal pain

4 (3.33)3 (2.5)

1 (0.83)

13 (10.38)12 (10.00)

2 (1.66)

0.040.030.99


1 (0.83)

4 (3.33)

0.36

Haemodynamic measures

Increase in diastolic blood pressure at 60 min from baseline, mmHg† 2.6 ± 1.0 3.5 ± 1.6 <0.0001

Pulse rate immediately after delivery (baseline), bpm† 83.7 ± 6.5 84.9 ± 5.8 0.13

Increase in pulse rate at 30 min from baseline, bpm† 2.2 ± 1.0 2.3 ± 1.1 0.6

Increase in pulse rate at 60 min from baseline, bpm† 2.8 ± 1.3 3.1 ± 1.4 0.08

Hypertension (blood pressure [140/90 mmHg]), n (%)‡

Immediately after delivery30 min after delivery60 min after delivery

2 (1.66)0 (0)0 (0)

4 (3.33)8 (6.66)7 (5.83)

0.680.0060.014

†Data are presented as n (%); ‡data are presented as mean ± standard deviation; bpm=beats per minute; MedDRA=Medical Dictionary for Regulatory Activities; n=number of women experiencing an adverse event; N=total number of women in each treatment group

4.5 EFFICACY AND SAFETY OF CARBETOCIN VERSUS MISOPROSTOL PLUS OXYTOCIN

4.5.1 Elgafor el Sharkwy 2013229

Design

This was a prospective, double-blind, double-dummy, randomised, controlled trial in 380 women with at least one risk factor for PPH and undergoing caesarean section. After the delivery of the infant, women were administered either a single IV bolus of 100 mcg carbetocin (n=190) delivered slowly over 30–60 seconds or 400 mcg misoprostol followed by an IV infusion of 20 IU oxytocin over 15 minutes (n=190). The misoprostol tablets were administered sublingually after spinal anaesthesia and prior to skin incision. The primary outcome was the need for additional uterotonics (Table 17).

A secondary outcome was estimated blood loss, which was determined by visual assessment, counting the number of used swabs and measuring the volume of aspirated blood.

Efficacy

There was no significant difference between the carbetocin group and sublingual misoprostol plus oxytocin group in terms of the requirement for additional uterotonics (13.7 vs 16.3%; p=0.27). In addition, there was no significant difference between the two groups in pre- and post-operative haemoglobin level change, estimated blood loss and incidence of blood transfusion (Table 40).

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Table 40. Primary and secondary outcomes were comparable between the carbetocin and misoprostol plus oxytocin groups

Outcomes

Carbetocin (N=190)

Misoprostol plus oxytocin (N=190)

p value

Need for additional uterotonics, n (%) 26 (13.7) 31 (16.3) 0.27†

Estimated blood loss, mL (range) 706 (625–980) 812 (761–1122) 0.86‡

Need for blood transfusions, n (%) 1 (0.5) 4 (2.1) 0.28§

Postpartum haemoglobin level, g/dL, mean (SD) 11.11 (1.12) 10.1 (1.24) 0.56‡

Haemoglobin difference (admission–postpartum), mean (SD) 1.51 (1.12) 1.34 (0.87) 0.81‡

Additional interventions n (%)Bilateral uterine artery ligation 1 (0.5) 3 (17) 0.39§

B-lynch suture 0 (0.0) 1 (0.5) 0.50§

†χ² test; ‡t-test; §Fisher exact test; n=number of women; N=total number of women in each treatment group; SD=standard deviation

Safety

Women in the sublingual misoprostol plus oxytocin group were significantly more likely to experience shivering compared with the carbetocin group (24.7 vs 3.1%; p<0.001), as well as fever (8.9 vs 1.1%; p<0.001). The incidence of flushing, vomiting, nausea, hypotension and headache were similar and not significantly different between the two groups (Table 41).

Table 41. Shivering and fever were more common in the misoprostol plus oxytocin group than in the carbetocin group


Carbetocin(N=190)

Misoprostol plus oxytocin(N=190)

p value

General disordersShiveringFever

6 (3.1)2 (1.1)

47 (24.7)17 (8.9)

<0.001<0.001


2 (1.1)

4 (2.1)

0.41

Gastrointestinal disordersNauseaVomiting

14 (7.4)9 (4.7)

17 (8.9)5 (2.6)

0.580.63

Vascular disordersFlushingHypotension

4 (2.1)5 (2.6)

5 (2.6)7 (3.7)

0.980.91


100

KEY POINTS Women receiving carbetocin need significantly less additional

uterotonic intervention compared with those receiving placebo62,221

Carbetocin is associated with a significantly lower need for additional uterotonics than oxytocin in women undergoing caesarean section62

Carbetocin is associated with significantly longer time before additional intervention compared with oxytocin in women undergoing caesarean section63

A significantly lower proportion of women treated with carbetocin require uterine massage compared with those receiving oxytocin222

More women treated with carbetocin experience blood loss ≤500 mL compared with those treated with oxytocin (81 vs 55%; p=0.05)64

Carbetocin has a comparable safety profile to oxytocin,62 and is associated with fewer adverse events than ergot alkaloids62,227

Blood loss is lower with carbetocin than with syntometrine in women undergoing vaginal delivery226,228

Carbetocin shows equivalent efficacy to misoprostol plus oxytocin, but with significantly fewer adverse events229

Data from one study suggest that carbetocin may lead to significantly lower levels of perceived post-operative pain compared with oxytocin66

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SUMMARY OF PRODUCT CHARACTERISTICS

1. Name of the Medicinal Product:PABAL 100 micrograms/mL solution for injection.

2. Qualitative and Quantitative Composition:Carbetocin 100 micrograms/mL.

Oxytocic activity: approximately 50 IU of oxytocin/vial

For a full list of excipients, see Section 6.1.

3. Pharmaceutical FormSolution for injection.

A clear colourless solution.

4. Clinical Particulars

4.1. Therapeutic IndicationPABAL is indicated for the prevention of uterine atony following delivery of the infant by Caesarean section under epidural or spinal anaesthesia.

4.2. Posology and Method of AdministrationPosology

Withdraw 1 mL of PABAL containing 100 micrograms carbetocin and administer only by intravenous injection, under adequate medical supervision in a hospital.

Paediatric population

No data available.

Method of administration

PABAL must be administered slowly, over 1 minute only after delivery of the infant by Caesarean section. It should be given as soon as possible after delivery, preferably before removal of the placenta. PABAL is intended for single use only. No further doses of carbetocin should be administered.

4.3. Contraindications• During pregnancy and labour before delivery of the infant.

CHAPTER V

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• Carbetocin must not be used for the induction of labour.

• Hypersensitivity to carbetocin, oxytocin or to any of the excipients listed in Section 6.1.

• Hepatic or renal disease.

• Cases of pre-eclampsia and eclampsia.

• Serious cardiovascular disorders.

• Epilepsy.

4.4. Special Warnings and Precautions for UseCarbetocin is intended for use only at well equipped specialist obstetrics units with experienced and qualified staff available at all times.

The use of carbetocin at any stage before delivery of the infant is not appropriate because its uterotonic activity persists for several hours after a single bolus injection. This is in marked contrast to the rapid reduction of effect observed after discontinuation of an oxytocin infusion.

In case of persistent uterine bleeding after administration of carbetocin the cause must be determined. Consideration should be given to causes such as retained placental fragments, inadequate emptying or repair of the uterus, or disorders of blood coagulation.

Carbetocin is intended for single administration only. It must be administered slowly over 1 minute. In case of persisting uterine hypotonia or atonia and the consequent excessive bleeding, additional therapy with oxytocin and/or ergometrine should be considered. There are no data on additional doses of carbetocin or on the use of carbetocin following persisting uterine atony after oxytocin.

Animal studies have shown carbetocin to possess some antidiuretic activity (vasopressin activity: <0.025 IU/vial) and therefore the possibility of hyponatraemia cannot be excluded, particularly in patients also receiving large volumes of intravenous fluids. The early signs of drowsiness, listlessness and headache should be recognised to prevent convulsions and coma.

In general, carbetocin should be used cautiously in the presence of migraine, asthma and cardiovascular disease or any state in which a rapid addition to extracellular water may produce hazard for an already overburdened system. The decision of administering carbetocin can be made by the physician after carefully weighing the potential benefit carbetocin may provide in these particular cases.

Specific studies have not been undertaken in gestational diabetes mellitus.

The efficacy of carbetocin has not been assessed following vaginal delivery.

4.5. Interaction with Other Medicinal Products and Other Forms of Interaction

During clinical trials, carbetocin has been administered in association with a number of analgesics, spasmolytics and agents used for epidural or spinal anaesthesia, and no drug interactions have been identified.

Specific interaction studies have not been undertaken.

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Since carbetocin is closely related in structure to oxytocin, the occurrence of interactions known to be associated with oxytocin cannot be excluded:

Severe hypertension has been reported when oxytocin was given 3 to 4 hours following prophylactic administration of a vasoconstrictor in conjunction with caudal-block anaesthesia.

During combination with ergot-alkaloids, such as methylergometrine, oxytocin and carbetocin may enhance the blood pressure enhancing effect of these agents. If oxytocin or methylergometrine are administered after carbetocin there may be a risk of cumulative exposure.

Since it has been found that prostaglandins potentiate the effect of oxytocin, it is expected that this can also occur with carbetocin. Therefore, it is not recommended that prostaglandins and carbetocin be used together. If they are concomitantly administered, the patient should be carefully monitored.

Some inhalation-anesthetics, such as halothane and cyclopropane may enhance the hypotensive effect and weaken the effect of carbetocin on the uterus. Arrhythmias have been reported for oxytocin during concomitant use.

4.6. Fertility, Pregnancy and LactationPregnancy

Carbetocin is contraindicated during pregnancy and must not be used for the induction of labour (see Section 4.3).

Breastfeeding

No significant effects on milk let-down have been reported during clinical trials. Small amounts of carbetocin have been shown to pass from plasma into breast milk of nursing women (see Section 5.2). The small amounts transferred into colostrum or breast milk after a single injection of carbetocin, and subsequently ingested by the infant are assumed to be degraded by enzymes in the gut.

4.7. Effects on Ability to Drive and Use MachinesNot relevant.

4.8. Undesirable EffectsThe adverse events observed with carbetocin during the clinical trials were of the same type and frequency as the adverse events observed with oxytocin when administered after Caesarean section under spinal or epidural anaesthesia (Table 42).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.*

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Table 42. Adverse events observed with carbetocin during the clinical trials

System organ class

Very common≥ 1/10

Common≥ 1/100 and < 1/10

Blood and lymphatic system disorders Anaemia

Nervous system disorders Headache, tremor Dizziness

Vascular disorders Hypotension, flushing

Respiratory, thoracic and mediastinal disorders Chest pain, dyspnoea

Gastrointestinal disorders Nausea, abdominal pain Metallic taste, vomiting

Skin and subcutaneous tissue disorders Pruritus

Musculosceletal and connective tissue disorders Back pain

General disorders and administration site conditions Feeling of warmth Chills, pain

In the clinical trials sweating and tachycardia were reported as sporadic cases.

4.9. OverdoseOverdosage of carbetocin may produce uterine hyperactivity whether or not due to hypersensitivity to this agent.

Hyperstimulation with strong (hypertonic) or prolonged (tetanic) contractions resulting from oxytocin overdose can lead to uterine rupture or postpartum haemorrhage.

Overdosage of oxytocin may lead to hyponatraemia and water intoxication in severe cases, especially when associated with excessive concomitant fluid intake. As carbetocin is an analogue of oxytocin, the possibility of a similar event cannot be excluded.

Treatment of overdosage of carbetocin consists of symptomatic and supportive therapy. When signs or symptoms of overdosage occur oxygen should be given to the mother. In cases of water intoxication it is essential to restrict fluid intake, promote diuresis, correct electrolyte imbalance, and control convulsions that may eventually occur.

5. Pharmacological Properties

5.1 Pharmacodynamic PropertiesPharmacotherapeutic group: Oxytocin and analogues

ATC code: H01BB03

The pharmacological and clinical properties of carbetocin are those of a long acting oxytocin agonist.

Like oxytocin, carbetocin selectively binds to oxytocin receptors in the smooth muscle of the uterus, stimulates rhythmic contractions of the uterus, increases the frequency of existing contractions, and raises the tone of the uterus musculature.

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On the postpartum uterus, carbetocin is capable of increasing the rate and force of spontaneous uterine contractions. The onset of uterine contraction following carbetocin is rapid, with a firm contraction being obtained within 2 minutes.

A single 100 micrograms intravenous dose of carbetocin administered after the delivery of the infant is sufficient to maintain adequate uterine contraction that prevents uterine atony and excessive bleeding comparable with an oxytocin infusion lasting for several hours.

5.2. Pharmacokinetic PropertiesCarbetocin shows a biphasic elimination after intravenous administration with linear pharmacokinetics in the dose range of 400 to 800 micrograms. The terminal elimination half-life is approximately 40 minutes. Renal clearance of the unchanged form is low, with <1% of the injected dose excreted unchanged by the kidney.

In 5 healthy nursing mothers, plasma carbetocin concentrations were detectable by 15 min and peaked at a maximum of 1035 ± 218 pg/mL within 60 min. Peak concentrations in milk were approximately 56 times lower than in plasma at 120 min.

5.3. Preclinical Safety DataNon-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicicology and genotoxicity. A reproductive toxicity study in rats, with daily drug administration from parturition to day 21 of lactation, showed a reduction in offspring body weight gain. No other toxic effects were observed. The indication did not warrant studies on fertility or embryotoxicity.

Carcinogenicity studies have not been performed with carbetocin due to the single dose nature of the indication.

6. Pharmaceutical Particulars

6.1. List of ExcipientsL-methionine

Succinic acid

Mannitol

Sodium hydroxide for pH adjustment

Water for injections

6.2. IncompatibilitiesIn the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

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6.3. Shelf-life2 years.

Shelf life after first opening the container:

After first opening the vial: the solution should be used immediately.

6.4. Special Precautions for StorageKeep vials in the outer carton, in order to protect from light. Store below 30°C. Do not freeze.

6.5. Nature and Contents of ContainerType I glass vials (2R) with type 1 bromobutyle stoppers with aluminium crimp cap containing 1 mL of solution for injection.

Packs of 5 vials.

6.6. Special Precautions for DisposalPABAL is for intravenous use only.

Only clear solutions practically free from particles should be used.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder<To be completed nationally>

<Name and address>

8. Marketing Authorisation Number(s)<To be completed nationally>

9. Date of First Authorisation/Renewal of the Authorisation<To be completed nationally>

10. Date of Revision of the Text<To be completed nationally>

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SUMMARY OF KEY POINTS Carbetocin is an injectable, long-acting, structural analogue

of the naturally-occurring human hormone oxytocin, with the pharmacological profile of a long-acting oxytocin receptor agonist61

A single IV injection of carbetocin achieves uterine activity within 2 minutes and lasts approximately 1 hour55

Women receiving a single dose of carbetocin need significantly less additional uterotonic intervention compared with those receiving placebo or oxytocin long IV infusion45,62

One trial has shown that more women receiving carbetocin experienced a blood loss of ≤500 mL, compared with women receiving oxytocin (81 vs 55%; p=0.05)64

Carbetocin has a similar safety profile to oxytocin and a superior safety profile to ergot alkaloids62

Carbetocin may be associated with significantly lower levels of perceived post-operative pain following caesarean section than oxytocin66

Carbetocin is well tolerated, exhibiting both the safety of oxytocin and the longer duration of ergot alkaloids62

The single injection administration eliminates the need for prolonged IV infusion with infusion systems, which involves appropriate training of clinical staff and regular monitoring of patients throughout the duration of the IV infusion13,37-41,46–48

A room temperature-stable formulation of carbetocin eliminates the cold-chain barrier to use in low-resource settings and may reduce the cost of distribution and storage61

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CONCLUSIONSEvery year, PPH contributes a major proportion of worldwide maternal mortality and morbidity.1 The incidence and consequences of PPH can be effectively reduced by proper intervention and active management of the third stage of labour.5

Most cases of PPH result from uterine atony.19,20 Uterotonic drugs, such as oxytocin, ergot alkaloids and prostaglandins, have an important role to play in the active management of the third stage of labour and, as a consequence, in the prevention of uterine atony-induced PPH.5,23 However, each of these existing therapies, while effective in preventing uterine atony and PPH, have some drawbacks. Both ergot alkaloids and prostaglandins are associated with a higher incidence of side effects compared with oxytocin;27–29,153 consequently, oxytocin is the preferred uterotonic drug for PPH prevention.10–14,23,44,75

However, there is no consistent administration method or dose for oxytocin. The labels from some European countries (UK, France, Italy, Spain and Germany) recommend both IM and IV injections, and doses ranging from 5 to 40 IU.31–35 In line with the inconsistent information from the labels, several routes of administration and dosages are used in clinical practice and recommended by major international and local guidelines,10,11,13,14,36–44 including prolonged IV infusions of 4, 6, 8 and 16 hours.11,13,37,38,40,41,44,45

When a drug is administered via a continuous IV infusion, clinical staff require appropriate training and need to regularly monitor their patients throughout the IV infusion, as recommended, for example, by the Royal College of Nursing,48 and also reinforced by the MHRA, which found 1085 incidents involving infusion pumps over a 5-year period in the UK.46 Moreover, many cases of hyponatraemia associated with IV administration of oxytocin have been reported.179–190 Indeed, oxytocin has an antidiuretic effect,177 which can be explained by the high structural similarity with vasopressin197,198 and the affinity to the vasopressin V2 receptor205,214 that mediates the antidiuretic effect of vasopressin.200

These shortcomings of existing uterotonic agents provided the rationale behind the development of carbetocin, a long-acting synthetic analogue of human oxytocin. Uterine activity after IV administration of carbetocin occurs within 1–2 minutes and lasts for approximately 1 hour.55 Carbetocin is equally effective as oxytocin in reducing the risk of PPH or severe PPH, and has a similar safety profile.62 It is also comparable to ergot alkaloids and misoprostol in preventing PPH, but presents a better adverse events profile.62,229 In addition, carbetocin shows several advantages in women undergoing caesarean section as compared with oxytocin: it significantly reduces the need for additional uterotonics and uterine massage,62,222 the time to further uterotonic treatments (when needed) is significantly increased,63 it is associated with more women experiencing blood loss ≤500 mL (81 vs 55%; p=0.05)64 and it has been reported in one study to be associated with significantly lower levels of perceived post-operative pain.66 In vitro studies have shown that carbetocin is much less potent than oxytocin at the human vasopressin V2 receptor.214

A fixed and consistent regimen of 100 mcg of carbetocin given as a single IV injection over 1 minute61 is simple and convenient. Carbetocin does not require prolonged infusion owing to its longer half-life in women (approximately 40 minutes versus 3–5 minutes for oxytocin)58–60 and thus regular monitoring is not needed. In contrast to oxytocin, the carbetocin dose of 100 mcg administered via a single IV injection is uniformly recommended by labels and guidelines,12,13,15,16,44,61,74,141–143 and has been consistently used in the vast majority of randomised controlled trials.45,63–65,221–230

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In addition, carbetocin is now available as a new room temperature-stable formulation and in a more convenient vial presentation.61 This eliminates the cold-chain considerations involved in therapy with oxytocin and ergot alkaloids. Based on the results obtained in stability studies, this formulation has a shelf-life of 24 months at 30ºC and 75% humidity,61,212 which would be helpful in low-income countries where cold-chain storage and transport may not be available.209

In conclusion, carbetocin is an effective option for the prevention of PPH and provides the above-described improvements over the existing uterotonic agents.12,13,44,62,141

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Date of preparation: May 2015.PL/1317/2014/CH3

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