Carbetocin In PPH_

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1. Carbetocin In PPH Dr.Rajendrasing Pardeshi . President,AMOGS

2. CV- Dr.Rajendrasing Pardeshi 28 Papers presented (20 in National & 7 in International conferences). 7 times Best Paper Awardee in FOGSI's AICOG conferences Was faculty in AOCOG 2011,Taipei and AOCOG 2013, Bangkok Was Faculty at FIGO 2006, KualaLumpur & FIGO 2012, Rome (Italy) Was Chairperson of Food & Drugs Committee, FOGSI (2012-14) & awarded Dr. Hansotiya Best Committee Award. Was VP-FOGSI (2019-20) Now VP-AMOGS (2020-22) President AMOGS (2022-24)

3. Post-Partum Haemorrhage (PPH) It is the main cause of maternal death worldwide Postpartum hemorrhage (PPH) is a blood loss >500 Ml within 24 hours after vaginal delivery or >1000 mL after cesarean delivery Obstet Gynecol. 2011 Jan;117(1):21-31 Semin Ultrasound CT MRI 00:1-10; Obstetrics , Gynaecology and Reproductive Medicine, https://doi.org/10.1016/j.ogrm.2020.05.002 Categories of post-partum blood loss Blood Loss MINOR MAJOR 500 ml 1000 ml 2 000 ml SEVERE MODERATE

4. Maternal Mortality and PPH PPH remains a major cause of both maternal mortality and morbidity worldwide In developing countries - Estimated mortality rate of 140,000 per year or 1 maternal death every 4 minutes WHO estimates that of the 5,29,000 maternal death occurring every year 1,36,000 or 25.7% of death takes place in India and two third of these maternal death occur after delivery, PPH being the most commonly reported complication. J Clin Diagn Res.  2017 Feb; 11(2): QE01–QE05.

5. Causes of PPH : FOUR “T” The most common cause of postpartum hemorrhage is uterine atony , which results from poor contraction of the uterus after childbirth Medicine (Baltimore). 2019 Nov; 98(47): e17911, Am Fam Physician. 2017 Apr 1;95(7):442-449

6. Uterine Atony Uterine atony is defined as failure of the uterus to contract adequately following delivery This is the most common cause of PPH and an obstetric emergency. Risk Factors Factor related with uterine distention Multiple pregnancy Labor related Factors Induction of labor Prolong labor Oxytocin augmentation Use of uterine relaxants Deep anesthesia Magnesium sulphate Intrinsic Factors Previous PPH history Obesity Age >35years Seminars in Perinatology.2009;33(2):82-87 Am Fam Physician. 2017;95(7):442-449 Globally, this is one of the top 5 causes of maternal mortality

7. It is important to limit the amount of hemorrhage to the minimum possible level World Health Organization (WHO) suggested the active management of the Third Stage of Labor

8. Pharmacotherapy for PPH The administration of uterotonic medication soon after the delivery of fetus is an essential part of the Active Management of Third Stage of Labor (AMTSL) Class Drugs Oxytocin and its analogue Oxytocin Carbetocin Ergot alkaloids Ergonovine maleate Methylergonovine Prostaglandins Carboprost Misoprostol Dinoprostone Best Pract Res Clin Obstet Gynaecol . 2019 Nov;61:3-14.

9. Current treatment options to manage PPH Am Fam Physician . 2017;95(7):442-449 .

10. Carbetocin Carbetocin is an analogue of oxytocin, and its action is similar to that of oxytocin -- it causes contraction of the uterus. Elsevier,2016,P440-443 BJOGJuly 2010 Volume117, Issue8, 929-936

11. Mechanism of action Carbetocin IP 3 : inositol triphosphate; Ca 2 + : calcium ion; 5-HT : 5-hydroxytryptamine ; α 1: alpha-1; DAG : diacylglycerol Carbetocin selectively binds to oxytocin receptors Stimulates rhythmic contractions of the uterus IP3 promotes release of Ca2+ from intracellular cells ↑ intracellular calcium F ormation of calcium- camodulin complex Best Pract Res Clin Obstet Gynaecol . 2019 Nov;61:3-14.

12. Pharmacodynamics On the postpartum uterus, carbetocin is capable of increasing the rate and force of spontaneous uterine contractions Onset of action of carbetocin is rapid after IV/IM , with a firm contraction being obtained within 2 minutes A single 100mcg IV/IM administered after the delivery of the infant is sufficient to maintain adequate uterine contraction Prescribing Information

13. Pharmacokinetics Parameters Absorption After intramuscular administration, Peak concentrations are reached after 30 minutes and the mean Bioavailability is 77%. Distribution Detectable in breast milk (small amount) Excretion <1% of the injected dose excreted unchanged by the kidney Terminal elimination half-life 33 minutes after intravenous administration 55 minutes after intramuscular administration Prescribing Information

14. Dosage Prescribing Information Condition Dosage Caesarean section under epidural or spinal anaesthesia: 1 ml containing 100 mcg carbetocin and administer only by intravenous injection , under adequate medical supervision in a hospital. Vaginal delivery: 1 ml containing 100 mcg carbetocin and administer by intravenous injection or intramuscular injection , under adequate medical supervision in a hospital * For intravenous administration carbetocin must be administered slowly, over 1 minute. Carbetocin is intended for single use only & No further doses of carbetocin should be administered

15. Clinical Evidence

16. Heat-Stable Carbetocin versus Oxytocin in PPH Prevention CHAMPION Trial Randomized , double-blind, noninferiority trial 23 sites in 10 countries 29,645 women with PPH after Vaginal Birth Intervention Heat-stable carbetocin 100mcg IM Vs. Oxytocin (at a dose of 10 IU) administered immediately after vaginal birth There were two primary outcomes: P roportion 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 Widmer M et al. N Engl J Med. 2018 Aug 23;379(8): 743-752

17. Primary outcome 1: 14.5% in the carbetocin group vs 14.4% in the oxytocin group Consistent with non-inferiority of carbetocin Primary outcome 2: 1.51% in the carbetocin group vs 1.45% in the oxytocin group The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between groups Widmer M et al. N Engl J Med. 2018 Aug 23;379(8): 743-752 Heat-stable carbetocin performed similarly to oxytocin in preventing blood loss of at least 500 ml or use of other uterotonic agents

18. Carbetocin versus oxytocin in caesarean section with high risk of post-partum haemorrhage Method : Prospective , case-control study N = 102 women undergoing elective CS having risk factors for primary PPH Carbetocin group (group A) : 100 μg IV at delivery of the anterior shoulder Control group (group B) : 20 IU of oxytocin + 0.9% Nacl solution IV (150 ml/ hour) Primary outcome : Evaluation of immediate haemodynamic effects of carbetocin administration Need for additional uterotonic agents Secondary outcome: Drop in haemoglobin level, T he uterine tone, The uterine fundal state and the diuresis . Journal of Prenatal Medicine 2013 ; 7 (1): 12-18

19. Result : Maternal blood loss Journal of Prenatal Medicine 2013 ; 7 (1): 12-18 Carbetocin (A) Oxytocin (B) P value During caesarean section n° (%) n° (%) < 500 ml 39 (76.5) 35 (68.6) 0.18 500- 1000 ml 12(23.5) 12 (29.4) > 1000 ml 0 (0.0) 4(7.8) 2h after caesarean section < 500 ml 50 (98.0) 50 (98.0) 1.00 500- 1000 ml 1 (2.0 ) 1 (2.0 ) 1000 ml 12h after caesarean section < 500 ml 51 (100.0) 51 (100.0) 1.00 500- 1000 ml 0 (0.0) 0 (0.0) 1000 ml 0 (0.0) 0 (0.0) 24h after caesarean section < 500 ml 51 (100.0) 51 (100.0) 1.00 500- 1000 ml 0 (0.0) 0 (0.0) 1000 ml 0 (0.0) 0 (0.0)

20. Carbetocin versus oxytocin in caesarean section with high risk of post-partum haemorrhage Uterine tone Position of the uterine fundus to the umbilical point (UP ) Result : * statistically significant Journal of Prenatal Medicine 2013 ; 7 (1): 12-18 Single injection of carbetocin appears to be more effective than a continuous infusion of oxytocin to prevent the PPH, with a similar haemodynamic profile and minor antidiuretic effect

21. Randomized controlled trial comparing carbetocin, misoprostol, and oxytocin for the prevention of PPH following an Elective cesarean delivery Methods : Prospective randomized double-blind trial N= 270 Patient Intervention: Carbetocin group: 100 μg /ml Misoprostol group : Two sublingual misoprostol tablets (each tablet 200 μg ) Oxytocin group : single 1-ml ampoule of oxytocin (10 IU/ml) Primary Outcome Occurrence of uterine atony necessitating additional uterotonics International Journal of Gynecology and Obstetrics xxx (2016) xxx – xxx

22. Results: Outcome measure Carbetocin -treated patients (n = 88) Misoprostol-treated patients (n = 89) Oxytocin-treated patients (n = 86) Additional uterotonics 5 (6) 20 (22) 11 (13) Blood loss, mL 437 (168–1194) 583 (178–1184) 439 (188–1079) Bleeding of 500–1000 mL 18 (20) 42 (47) 29 (34) Bleeding of 1000 mL 3 (3) 7 (8) 5 (6) Hb decrease, g/ dL 6.0 (3.0–16.0) 10.0 (–3.0 to 19.0) 7.0 (–3.0 to 16.0) Additional uterotonics were less frequently needed by patients treated with carbetocin Carbetocin appears to be an attractive alternative to compared to oxytocin and misoprostol for the prevention of atonic PPH following cesarean delivery International Journal of Gynecology and Obstetrics xxx (2016) xxx – xxx

23. Carbetocin Versus Oxytocin for PPH in Patients With Severe Preeclampsia A Double-Blind Randomized Controlled Trial Prospective double-blind randomized Controlled trial N= 60 women with severe preeclampsia J Obstet Gynaecol Can 2011;33(11):1099–1104 Primary and secondary outcomes Carbetocin 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 C avity , n (%) 2 (8) 4 (13.8) 0.41 Postpartum hemoglobin level, g/ dL , mean (SD) 10.8 (1.68) 11.14 (1.76) 0.56 Hemoglobin 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 Carbetocin is as effective as oxytocin in preventing postpartum bleeding in women with severe preeclampsia, with no alterations in hemodynamic status and with few side effects

24. Carbetocin Vs Oxytocin For PPH Prevention: A Meta-analysis M eta-analysis of 5 RCT including 30,314 women T here was no significant difference between carbetocin and oxytocin in blood loss ≥500ml in women undergoing vaginal delivery. Jin XH et al. Medicine (Baltimore). 2019 Nov;98(47):e17911.

25. WHO recommendations on the use of uterotonics for the prevention of postpartum haemorrhage (PPH) CARBETOCIN is recommended by WHO as an effective uterotonic in its 2018 guidelines

26. FIGO recommendations Drug regimens for prevention and treatment of PPH - June 2021 International Federation of Gynecology and Obstetrics, International Confederation of Midwives.  Joint statement of recommendation for the use of uterotonics for the prevention of postpartum haemorrhage .  2021. Available from:  www.figo.org/joint-statement-recommendation-uterotonics-prevention-pph

27. RCOG Postpartum Haemorrhage , Prevention and Management (Green-top Guideline No. 52) Published. 16/12/2016

28. October 2009 (Replaces No. 88, April 2000)

29. How carbetocin is better than oxytocin ?

30. Oxytocin Carbetocin Short half-life: 3-17mins Long half-life : 40 minutes after IV injection Four-fold longer uterotonic activity that precludes the necessity of a continuous infusion Continuous infusion is required due to achieve sustained uterotonic activity Single injection of 100mcg is effective Reduces need of additional uterotonic agent compared to oxytocin following both Cesarean and high-risk vaginal delivery Does not possess satisfactory real-world efficacy, particularly in hot low-and middle-income countries and regions Storage temperature: 2-8 ◦C (Cold chain requirement) Carbetocin is promising alternative to oxytocin (first-line drug) for prevention of PPH Stable at 30 ◦C Larger doses are associated with severe water intoxication with convulsions Possess mild diuretic action Oxytocin Vs Carbetocin Prenat Med. 2013 Jan;7(1): 12-8 Best Pract Res Clin Obstet Gynaecol . 2019 Nov;61:3-14 .

31. Summary PPH remains the leading cause of maternal morbidity and mortality worldwide. Uterine atony is the most common cause of PPH Carbetocin is a long‐acting synthetic analogue of oxytocin Carbetocin is promising alternative to oxytocin (first-line drug) for prevention of PPH Non-inferior to oxytocin with single dose administration New formulation with good stability at 30 degree temperature Currently licensed for active management of third stage of labor

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