The document discusses various uterotonic drugs used to prevent postpartum hemorrhage (PPH), including their advantages and disadvantages. Oxytocin requires multiple doses and cold storage but has a short duration. Ergometrine and misoprostol are associated with more side effects. Carboprost also requires cold storage and has safety concerns. A new heat-stable formulation of carbetocin called RTS carbetocin addresses these issues, providing the benefits of carbetocin with room temperature stability. Clinical trials found RTS carbetocin to be non-inferior to oxytocin in preventing excessive bleeding with fewer additional uterotonic requirements. Its inclusion in WHO guidelines supports its role in

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FOGSI 2014. Consensus Statement for Prevention of PPH. Accessed online on dated 23 July 2021 from https://www.fogsi.org/wp-content/uploads/2015/11/pph.pdf

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Oxytocin
• Requires special
storage conditions: 2-
8°C
• Multiple dosing
regimen
• Short acting; multiple
doses may be required
• Overdose or prolonged
use can cause water
intoxication
• Prolonged use can
itself lead to uterine
atony
Ergometrine
• Requires special
storage conditions: 2-
8°C
• Associated with
significant increase in
side effects like
nausea, vomiting and
HT
• Needs to be avoided in
HDP, including chronic
HT
Misoprostol
• Less effective in
preventing PPH*
• More side effects, such
as shivering and
pyrexia*
• Associated with a
higher risk of severe
PPH and increased use
of additional
uterotonics*
• Use with caution in
patients with
cardiovascular disease*
Carboprost
• Requires special
storage conditions: 2-
8°C
• Associated with side
effects like vomiting,
diarrhea and
bronchospasm
• Needs to be avoided in
patients with asthma
or significant renal,
hepatic, or cardiac
disease
Syntometrine (Oxytocin+Ergometrin)- Combines the concerns of respective drugs
HT, hypertension; HDP, hypertensive disorders of pregnancy; * compared to oxytocin
Evensen A, et al. Am Fam Physician. 2017;95(7):442-449. Gulmezoglu AM, et al. Lancet. 2001 Sep 1;358(9283):689-95. Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017
Oct;130(4):e168-e186. FOGSI 2014. Consensus Statement for Prevention of PPH. Accessed online on dated 23 July 2021 from https://www.fogsi.org/wp-content/uploads/2015/11/pph.pdf

4. Questionable
efficacy
after drug
degradation
Associated side
effects
Require
special
storage
conditions
(2-8°C)
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Threats to Oxytocin Quality
Occur throughout the Supply
Chain for Oxytocin.
Threats to oxytocin quality
occur throughout
manufacturing,
procurement, distribution,
and storage
Lambert et al. Journal of Pharmaceutical Policy and Practice (2020) 13:14

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7.  Approved globally for medical use since last 2 decades; lately introduced in India
 Long-acting synthetic analogue of oxytocin with agonist properties
 Molecular structure different from oxytocin can lead to
 Enhanced stability (avoid the cleavage of aminopeptidase and disulfide compounds)
 Lower affinity for vasopressin V2 receptor
 Rapid onset of action (within 1–2 min)
 Prolonged duration of action (approximately 1 h)
 Safety profile comparable to oxytocin
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Liu et al., Maternal-Fetal Medicine 2020;2:2. Holleboom et al., Arch Gynecol Obstet 2013:287:1111–1117

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Oxytocin: Drawbacks
 Antidiuretic effects/water intoxication
 Multiple dosing regimen
 Short acting; repeat doses required
 Failure of PPH prophylaxis
 Stability and quality issues
Can be addressed by
carbetocin

9.  Carbetocin was as effective as oxytocin in prevention of PPH
 Carbetocin showed lesser mean blood loss in some studies
 Carbetocin enhanced early postpartum uterine involution in some studies
 Carbetocin showed fewer women requiring additional uterotonics in some studies
 Carbetocin showed fewer women requiring uterine massage in some studies
 Carbetocin showed lower blood transfusion rates in some studies
 Carbetocin showed lower incidence of post partum anemia in some studies

10.  Carbetocin showed lesser mean blood loss in some studies
 Carbetocin showed fewer women requiring additional uterotonics in some studies
 Carbetocin showed lower incidence of post partum anemia in some studies
 Carbetocin was associated with lesser incidence of nausea and vomiting
 Syntometrine was associated with increase in systolic and diastolic blood pressure

11.  Carbetocin was more effective than misopristol in prevention of PPH
 Carbetocin was associated with lower duration of 3rd stage of labour in some studies
 Carbetocin showed lesser mean blood loss in some studies
 Carbetocin showed fewer women requiring additional uterotonics in some studies
 Carbetocin showed fewer women requiring uterine massage in some studies
 Carbetocin showed lower blood transfusion rates in some studies in some studies
 Adverse effects were more common in the misoprostol group

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Long acting; does not require prolonged IV infusion
Administered via a single IV injection, with no need for repeated injections
Well established dose; validated for the prevention of PPH
Lower affinity to the vasopressin V2 receptor compared with oxytocin
Possibly less blood loss & requirement of additional oxytocics
Stable at room temperature
Seems like an ideal uterotonic, but lacks room temperature stability
Carbetocin

13.  Novel room temperature stable formulation of carbetocin
 Same active ingredients, but differs in its excipients in order to increase stability
 Devoid of need for cold chain maintenance and storage issues
 Shelf-life of 24-36 months at 30oC and 75% humidity
 Provided in a vial
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Characteristic Description
Onset of action • Within 2 minutes
Half-life • 33 minutes (IV)
• 55 minutes (IM)
Duration of action • 60 minutes (IV)
• 119 minutes (IM)
Dosage and mode of
administration
• 100 mcg administered IV (slowly over 1 minute) or IM
• Must only be administered after delivery of the infant, and as soon
as possible after delivery, preferably before the delivery of the
placenta
• Single use only (No further doses should be administered)
Storage Room temperature, ≤30°C and 75% relative humidity
Pabal Summary of Product Characteristics 2019. As accessed on dated 23 July 2021 from https://www.medicines.org.uk/emc/product/172/smpc#POSOLOGY
Pabal RTS Monograph. As accessed on dated 23 July 2021 from https://www.ferring.de/assets/Bilddaten-und-verlinkte-Dateien-www.ferring.de/Arzneimittel/PABAL/PABAL-RTS-Monograph-5.6.15.pdf

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Long acting; does not require prolonged IV infusion
Administered via a single IV injection, with no need for repeated injections
Well established dose that has been validated for the prevention of PPH
Lower affinity to the vasopressin V2 receptor compared with oxytocin
Possibly less requirement of additional oxytocics
Stable at room temperature
Provides all advantages of Carbetocin with further benefits of room temperature stability

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17.  Conducted by the WHO*
 Randomized, multicentric, double- blind, active-controlled, noninferiority trial
 23 sites in 10 countries
 Primary outcomes:
 Proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents, and
 Proportion of women with blood loss of at least 1000 ml
CHAMPION TRIAL
N = 29645 women
RTS Carbetocin 100
mcg administered
immediately after
vaginal birth
N = 14823
Oxytocin 10 IU
administered
immediately after
vaginal birth
N = 14822
*in collaboration with Ferring and MSD for Mothers
(Carbetocin HAeMorrhage PreventION)

18. 14.5
1.51
10.4
1.6
14.4
1.45
10.4
1.3
0
2
4
6
8
10
12
14
16
Blood loss
>500ml or use of
additional
uterotonic agent
Blood loss > 1000
ml
Use of additional
uterotonic
agents
Blood
transfusion
Primary and secondary outcomes
Carbetocin Oxytocin
N Engl J Med. 2018 Aug 23;379(8):743-752
 RTS carbetocin was non-inferior to oxytocin for
the prevention of blood loss of at least 500 ml
or the use of additional uterotonic agents
 No significant differences between the two
groups in other measures of bleeding or in
adverse effects
 These data inform care of women in parts of
the world where a lack of heat stability is a
barrier to the effective prevention of
postpartum hemorrhage

19. Advantages1
 Clinical data generated in Indian
population
 RTS carbetocin has shown efficacy and
tolerability at par with oxytocin
Limitations2
 The trial may underestimate the benefit
expected with heat-stable carbetocin use
in real-life settings where oxytocin may
have degraded due to exposure to higher
temperatures.
1. N Engl J Med. 2018 Aug 23;379(8):743-752 2. https://www.who.int/news/item/27-06-2018-who-study-shows-drug-could-save-thousands-of-women%E2%80%99s-lives

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https://www.who.int/news/item/27-06-2018-who-study-shows-drug-could-save-thousands-of-women%E2%80%99s-lives

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RTS carbetocin has been added to 21st WHO Essential Medicines List (2019)
WHO Model List of Essential Medicines. https://list.essentialmeds.org/?query=carbetocin

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The GDG noted that both heat-stable and non-heat-stable formulations of
carbetocin are available.
The heat-stable formulation differs from the non-heatstable formulation only in
its excipients.
Heat-stable carbetocin does not require refrigeration and therefore eliminates
the costs associated with refrigerated storage and transport for non-heat-stable
uterotonics.
GDG, Guideline Development Group

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FIGO, The International Federation of Gynecology and Obstetrics
ICM, The International Confederation of Midwives
FIGO and ICM launch joint statements of recommendation for the prevention and treatment of PPH. As accessed on 23 July 2021 from https://www.figo.org/figo-icm-pph-statements

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Considerations in selecting a uterotonic for PPH prevention
BMJ Global Health 2019;4:e001466.

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A similar sort of pharmacoeconomic evaluation should be considered in Indian set-up taking into account
costs of additional uterotonics, blood transfusion, extended hospital stay and resultant morbidities in
Carbetocin versus Oxytocin recipients for PPH prevention
Luni Y, et al. Journal of Obstetrics and Gynaecology, 2017. DOI: 10.1080/01443615.2017.1284188

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Caceda SI, et al. J Comp Eff Res. 2018 Jan;7(1):49-55.

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28.  Stability of uterotonics requiring cold storage is a grave concern in India
 Carbetocin addresses most of the concerns with oxytocin; but still requires storage condition of 2-8°C
 RTS Carbetocin provides all the advantages associated with heat labile carbetocin while overcoming the
limitation of cold storage requirement
 Clinical data on RTS Carbetocin in Indian population is available from WHO’s CHAMPION trial
 Meta-analysis has shown potential benefits of Carbetocin vs Oxytocin
 Reduced blood loss
 Reduced requirement of additional uterotonics
 Reduced requirement of blood transfusion
 Lesser reduction in Hb levels
 RTS has been included in WHO essential medicine list and various guidelines
 RTS Carbetocin has added useful tool in the arsenal for PPH prevention in India
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29. Thank You!