Carbetocin: indications, efficacy safety

Irene Hoesli University hospital Basel

Spring meeting of SAOA Winterthur 17.04.2010 • PPH is the most important cause of maternal mortality in the developing world

• is responsible in 50%

• Important cause of maternal morbidity Maternal mortality in Switzerland 1995-2004

• 4,1/100 000 live birth • Haemorrhage (13/50) – Non Swiss nationality – Mean age 32 y

Fässler M et al Swiss Med Wkly 2010 Active management of third stage of labour

• Use of (syntometrine, ) • Clamping of the umbilical cord • Controlled traction of the cord • Massage of the uterus after delivery of the placenta Active management of third stage of labour

• PPH RR 0,32 ( 0,21-0,50 95% CI) • Blood transfusion RR 0,33 ( 0,21-0,52 95% CI) • Nausea, hypertension RR1,83 (1,51-2,23 95% CI)

Prendiville WJ CC database review, 2000 Issue 3 Carbetocin (Pabal ®)

• Long acting structural analog of oxytocin (Atke A et al Acta Endocrinol 1987) • Binds selectively to oxytocin receptors • Uterus: Produce tetanic followed by rhythmic uterine contractions • Breast: Stimulates the letdown of milk • Antidiuretic effect as structural similarity to • Influence cardiac and vascular tissues Indications

• Prevention of PPH – Elective and emergency CS • Off label use – Vag. delivery with risk factors • Exclusion – Preeclampsia, chronic heart, liver, kidney disease, epilepsia Efficacy Pabal Pabal Oxytocin Oxytocin IV IM IV IM

Start of 1,5 min < 2 min < 1 min < 2,5 min action 4-10 Half time 40 min min

Contraction 60± 18 119±69 16 min 30 min time min min

Hunter DJ et al Clin Pharmacol Ther 1992 RCT Dansereau et al, Am J Obstet Gynecol 1999

• Pat. with elective c-section (317 vs 318) – 100 ug Carbetocin iv vs standard bolus injection (5 IU) and 8- h infusion of Oxytocin (20 IU) • Primary outcome: need for additional oxytocin in – 4.7 vs 10.1% p< 0.5 OR 2.03 (95% CI 1.1-2.8) • Secondary outcome: delay between administration – 11 vs 120 min, p< 0,001

– Additional: Oxytocin, Ergomethrin, PG F2a RCT Dansereau et al, Am J Obstet Gynecol 1999

no difference in: • Headache • Nausea • Feeling of warmth • Metallic taste • Flushing • Sweating • Tremors • Vomiting Efficacy of carbetocin and oxytocin

80 P=0,04 P=0,02 70

60

50

40 carbetocin oxytocin 30 P<0,05

20

10

0 1 Boucher 1998 blood loss < add uterotonic2 uterine 200 ml 1 massage 3 2 Danserau 1999 3 Boucher 2004 Borruto F et al Arch Gynaecol Obstet 2009 Carbetocin vs Oxytocin/Ergometrin RCT Leung SW et al, BJOG 2006

• 300 women after vag. delivery > 34 wg – 100 ug Carbetocin im vs – 5 IU Oxytocin and 0.5 mg and 16-h infusion of Oxytocin (3x10 IU) • Primary outcome: drop in hematocrit level 48 h after delivery Leung SW et al BJOG 2006

CS VD Use of RR 0,44 (0,25- RR 0,93 (0,44- therapeutic 0,78 95%CI) 1,94 95%CI) uterotonics Need for uterine RR 0,38 (0,18- RR 0,70 (0,51- massage 0,80 95%CI) 0,94 95%CI)

Su LL et al Cochrane review 2007

Maximum tolerated dose

• The maximum tolerated dose is estimated to be 200 ug. N=45, Vag del, no

• Dose limiting adverse event – blood loss > 1000 ml – Need for blood transfusion – Additional oxytocic treatment (oxytocin, ) – Retained placenta

Van Dongen et al Eur J Obstet Gynecol Repro Biol 1998 Clinical issue

• Single injection 100 μg (1ml ) • as bolus • not diluted • Stored at refrigerator temperature (2- 8° C), protected from light est. blood age gravid para GA indication for CS birth weight loss add. Uterotonics

38 II II 37 +0 previous CS, on demand 2910 700 Oxytocin 5IU 28 I I 39 +3 on demand 3795 500 35 I I 38 +6 breech 3420 300 Oxytocin 5IU 36 III II 38 +6 previous CS, breach 2760 500 chorioamnionitis, IUGR, detal 24 I 0 26 +5 distress 750 500 Oxytocin 5IU, 1000ug 33 I 0 40 +4 pelvic dysproportion 3240 800 29 I 0 39 +0 on demand 3020 400 previous CS, Hx of Hysterotomia 36 VII V 38 +5 anterior 2855 500 36 I 0 29 +5 chorioamnionitis, breech, PPROM 1480 600 Oxytocin 25 IU, Cyclocapron 1g, Fibrinogen 1g, 46 V 0 38 +2 breech, Placenta increta 3570 2000 Novoseven 4,5 g, Bakri ballon 37 II 0 38 +0 di-di twins, breech 3135/3030 500 Oxytocin 5 IU 29 I 0 38 +5 breech,IUGR 2690 700 33 I 0 38 +2 breech 2835 700 30 I 0 31 +6 FFTS, monochorionic twins 1800/1410 800 Oxytocin 5 IU, Misoprostol 1000ug 36 I 0 38 +6 cervical myoma 3515 700 28 I 0 38 +3 uterus myomatosus 2975 800 33 I 0 38 +2 fetal distress 2750 500 31 II I 38 +4 posttraumatic stress disorder 2435 600 39 II I 39+0 previous CS 2995 500 Oxytocin Bolus Carbetocin Bolus 2 x 2.5 IE 100 ug Carbetocin vs Oxytocin Costs

• 5 x 1 A. Carbetocin à 100 ug 207.00 CHF – 1 A Carbetocin à 100 ug 41.40 CHF

• 5 x 1 A. Oxytocin à 5IE 3.65 CHF – 1 A Oxytocin à 5 IE 0.73 CHF Pabal 100 ug Oxytocin 45 IE 16 h contractions 16 h contractions 41 CHF 7 CHF

Less syringe,pads Additional uterotonics Less fundal pressure Summary (1)

• Carbetocin is associated with reduced need for uterine massage and reduced need for therapeutic uterotonics. • There is a trend towards less maternal side effects (nausea, vomiting) • The application might be less time consuming for the medical team and less uterine massage might be more convenient for the women Summary (2)

• Research in women with preeclampsia, gestational diabetes and for vaginal delivery • Carbetocin‘s contribution to emotional process post partum • Investigations for cost-effectiveness Thank you for your attention [email protected]