carbetocin versus oxytocin - qatar university

Oxytocin versus carbetocin for the prevention of postpartum hemorrhageprevention of postpartum hemorrhage

Hager ElGeed

PharmD Candidate

Qatar University College of Pharmacy

Outlines

o Postpartum hemorrage

o Current treatment options

o Oxytocin

o Carbetocino Carbetocin

o Evidence overview

o Final summary

o Economics consideration

o Recommendation

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Postpartum Hemorrhage

o Postpartum hemorrhage (PPH) is the leading cause of

maternal mortality

o PPH Definition:

� Excessive bleeding that makes the patient � Excessive bleeding that makes the patient

symptomatic and/or results in signs of hypovolemia

3Smith J, Ramus R. Postpartum hemorrhage. [online] Feb 13, 2012 [cited Feb 19 2012] Available from: URL:

http://emedicine.medscape.com/article/796785-overview


o All women who carry a pregnancy beyond 20 weeks’

gestation are at risk for PPH and its sequelae

o Maternal mortality rates have declined greatly in the

developed worlddeveloped world

� PPH remains a leading cause of maternal mortality in

developing countries

4Smith J, Ramus R. Postpartum hemorrhage. [online] Feb 13, 2012 [cited Feb 19 2012] Available from: URL:

http://emedicine.medscape.com/article/796785-overview


o Normally:

� In late pregnancy, uterine artery blood flow is 500

to 700 mL/min and accounts for about 15%of

cardiac outputcardiac output

�Uterine bleeding after delivery is controlled by

• Contraction of the myometrium

• Local decidual hemostatic factors: tissue factor,

type-1 plasminogen activator inhibitor, platelets

and circulating clotting factors

Postpartum hemorrhage. Uptodate online database. 2012. Available from: URL: www.uptodate.com

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o Pathophysiology

� The most common cause is uterine atony �failure of

the uterus to contract and retract following delivery

of the babyof the baby

� Trauma

� Coagulation defects

6Postpartum hemorrhage. Uptodate online database. 2012. Available from: URL:

www.uptodate.com

o Pathophysiology:


Postpartum hemorrhage prevention and management. American Family Physician. http://www.aafp.org/afp/2007/0315/p875.html

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Retained placenta Failure to progress during the second stage of labor

Placenta accreta Lacerations

Instrumental delivery Large for gestational age newborn

Risk factors:

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Instrumental delivery Large for gestational age newborn

Hypertensive disorders

Induction of labor

Others: placenta previa, history of previous PPH, obesity, high parity, precipitous labor, first stage of labor longer than 24 hours, uterine overdistention, uterine infection, and preeclampsia



� Death

� Fluid overload

� Hypovolemic shock and organ failure

� Abdominal compartment

� Death

� Fluid overload

� Hypovolemic shock and organ failure

� Abdominal compartment

� Anesthesia-related complications

� Sepsis, wound infection, pneumonia

� Venous thrombosis or

� Anesthesia-related complications

� Sepsis, wound infection, pneumonia

� Venous thrombosis or

Complications

� Abdominal compartment syndrome

� Anemia & transfusion-related complications

� Acute respiratory distress syndrome

� Abdominal compartment syndrome

� Anemia & transfusion-related complications

� Acute respiratory distress syndrome

� Venous thrombosis or embolism

� Unplanned sterilization due to need for hysterectomy

� Asherman syndrome (related to curettage if performed for retained products of conception)

� Venous thrombosis or embolism

� Unplanned sterilization due to need for hysterectomy

� Asherman syndrome (related to curettage if performed for retained products of conception)


www.uptodate.com

Treatment

o Initial interventions:

�Stabilization

� IV access

�Oxygen�Oxygen

�Baseline laboratory evaluation

�Non-pharmacological

• Uterine massage!


www.uptodate.com

Treatment

o Medications:

� Methylergonovine

� Carboprost tromethamine

� Misoprostol� Misoprostol

� Dinoprostone

� Oxytocin/ergometrine (Syntometrine)

� Oxytocin

� Carbetocin

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Oxytocin

Indirectly stimulates contraction of uterine

smooth muscle

Stored in the posterior pituitary

(neurohypophysis) in mammals

A nonapeptidehormone secreted by the neurons of the

supraoptic and paraventricular nuclei of the hypothalamus

AHFS drug information. 2011. Restricted access via: ezxproxy.qu.edu.qa

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Oxytocin

o Indications:

� To produce intense uterine contractions

� To reduce postpartum bleeding after expulsion of the

placentaplacenta

o Dose in PPH:

� I.M.: Total dose of 10 units after delivery of the placenta

� I.V.: 10-40 units by I.V. infusion in 1000 mL of intravenous

fluid at a rate sufficient to control uterine atony


www.uptodate.com

Oxytocin

Mechanism of

Action

Stimulates contraction of uterine smooth muscle• Increases intracellular calcium concentrations

• Mimics contractions of normal, spontaneous labor and transiently impeding uterine blood flow.

Absorption RapidAbsorption Rapid

Excretion Renal (small amounts unchanged)

Elimination Half

Life

Systemic: 1 to 6 min

Dosing Determined by uterine response and must be individualized and initiated at a low level

Drugpoints . 2011. Restricted access via: ezproxy.qu.edu.qa 14

Oxytocin

Side Effects

Mother Infant

Nausea, Vomiting, Cardiac dysrhythmia

Cardiac dysrhythmia Fetal bradycardia

Hypertensive episode Ventricular premature beats

Ventricular premature beats Neonatal jaundiceVentricular premature beats Neonatal jaundice

Water intoxication syndrome Low apgar score

Anaphylaxis Rare: convulsions in the newborn

Pelvic hematoma

Rare: Brain damage, Permanent central nervous system deficit, Permanentcoma, Subarachnoid hemorrhage

15Drugpoints . 2011. Restricted access via: ezproxy.qu.edu.qa

Carbetocin

o A long-acting analog of oxytocin

o Available in many countries

�No available in the US

o It appears to be as effective as oxytocin


www.uptodate.com

Carbetocin

o Indication:

1. Prevention of uterine atony and postpartum

hemorrhage following elective cesarean section under

anesthesia (epidural or spinal)anesthesia (epidural or spinal)


www.uptodate.com

Carbetocin

Mechanism of

Action

Carbetocin binds to oxytocin receptors present on the smooth musculature of the uterus:

• Rhythmic contractions of the uterus, increased frequency of existing contractions, and increased uterine tone

Absorption Rapid

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Duration IV: 1hr

Administration Administer as bolus I.V. injection over 1 minute only after delivery of infant has been completed by cesarean section. May administer before or after delivery of placenta.

Dosing I.V.: 100 mcg (single dose only)


Carbetocin

o Side effects

� As an analog, it has similar ADRs as oxytocin


www.uptodate.com

Evidence

Dansereau J, Joshi AK, Helewa ME, Doran TA, Lange IR, Luther ER, et al. Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean

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prevention of uterine atony after cesarean section. Am J Obstet Gynecol 1999 Mar;180(3 Pt 1):670-6.

Patients 694 patients undergoing elective cesarean section

Interventions A single 100 microg dose of carbetocin

Comparison A standard 8-hour infusion of oxytocin

Outcomes The primary outcome was the proportion of patients

requiring additional oxytocic intervention for uterine

atony

Dansereau J, Joshi AK, Helewa ME, Doran TA, Lange IR, Luther ER, et al. Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean section. Am J Obstet Gynecol 1999 Mar;180(3 Pt 1):670-6.

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Major Findings 1. The overall oxytocic intervention rate was 7.4%

2. The odds of treatment failure requiring oxytocic

intervention was 2.03 times higher in the oxytocin

group compared with the carbetocin group (32 of 318

(10.1%) versus 15 of 317 (4.7%), P < .05.)

Evidence

Borruto F, Treisser A, Comparetto C. Utilization of carbetocin for prevention of

postpartum hemorrhage after cesarean

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postpartum hemorrhage after cesarean section: a randomized clinical trial. Arch Gynecol Obstet 2009 Nov;280(5):707-12.

Patients 104 women who underwent elective C/S

Interventions Single 100 microg IV dose of carbetocin

Comparison A standard 2-h of 10 IU IV infusion of oxytocin

Outcomes The primary outcome was the proportion of patients requiring additional oxytocic intervention for uterine atony

Major Findings 1. 100 mcg IV of carbetocin was as effective as a

Borruto F, Treisser A, Comparetto C. Utilization of carbetocin for prevention of postpartum hemorrhage after cesarean section: a randomized clinical trial. Arch Gynecol Obstet 2009 Nov;280(5):707-12.

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Major Findings 1. 100 mcg IV of carbetocin was as effective as a continuous 2-h infusion of oxytocin

2. Mean blood loss after carbetocin was 30 ml less than after oxytocin (P = 0.5).

3. Uterotonic intervention was clinically indicated in two of the women (3.8%) receiving carbetocin compared to five of the women (9.6%) given an IV oxytocin infusion (P < 0.01).

Evidence

LL Su, YS Chong, M Samuel. Carbetocin for preventing postpartum haemorrhage

(Review). The Cochrane Library

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(Review). The Cochrane Library2012, 2: 1-88

Summary of the Review

Eleven studies were included in the analysis

Five were supported by pharmaceutical companies

Six trials compared carbetocin with oxytocin; four of these Six trials compared carbetocin with oxytocin; four of these were conducted for women undergoing caesarean deliveries, one was for women following vaginal deliveries and one did not state the mode of delivery clearly.

Four trials compared intramuscular carbetocin and intramuscular syntometrine for women undergoing vaginal deliveries.

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Summary of the Review

Dosing

• The carbetocin was administered as 100 µg intravenous dosage across the trials, while oxytocin was administered intravenously but at varied dosages

Need for

• Use of carbetocin resulted in a statistically significant reduction in the need for therapeutic uterotonics (risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44 to 0.88; four trials, 1173 women)

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Need for additional uterotonic

confidence interval (CI) 0.44 to 0.88; four trials, 1173 women) compared to oxytocin for those who underwent caesarean section, but not for vaginal delivery.

Other agents

• Comparison between carbetocin and syntometrine showed a lower mean blood loss in women who received carbetocin compared to syntometrine (mean difference (MD) -48.84 ml; 95% CI -94.82 to -2.85; four trials, 1030 women).

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Final summary

Medication Advantages Disadvantages

Oxytocin 1. Well known and studied (familiarity)

2. Can be used in normal delivery, C/S and also for induction of labor.

1. Short duration of action2. Frequent monitoring is

required (individualized dose)

Carbetocin 1. Fixed dose 1. In normal delivery it is not Carbetocin 1. Fixed dose2. Ease in administration3. Reasonably short duration of

action

1. In normal delivery it is not superior to oxytcoin

2. Indication is very specific (narrow spectrum)

3. More evidence is needed to support its use

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Economics considerations

o Cost-effectiveness of carbetocin was investigated by

one study published as an abstract, with limited data

o Costs of carbetocin versus oxytocin:

1. UK: £17.64 vs. £0.861. UK: £17.64 vs. £0.86

2. North America: $25.58 vs. $1.25

o The indirect cost!

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Recommendations

o Carbetocin 100 mcg is given by a single slow intravenous

injection.

o Carbetocin can be a reasonable alternative to oxytocin

in countries where it is available.in countries where it is available.

o Its efficacy in treating existing uterine atony is not well

documented.

o More studies are needed about its use in normal

deliveries

http://www.thedoctorschannel.com/view/carbetocin-may-be-more-potent-than-oxytocin-following-c-section-2/ 30

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carbetocin versus oxytocin - qatar university

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