A COLLABORATION OF THE WHO, FERRING AND MERCK FOR MOTHERS

• Ferring Pharmaceuticals and Merck for Mothers, MSD’s charitable initiative, approached the World Health Organization (WHO) in order to explore heat-stable carbetocin^2,3
• The CHAMPION trial, studied a heat-stable formulation of carbetocin vs. oxytocin and demonstrated that the heat-stable formulation of carbetocin was non-inferior to oxytocin in the proportion of women with blood loss ≥500 mL or the use of additional uterotonic agents; 14.5% carbetocin vs 14.4% oxytocin [relative risk,1.02; 95% CI, 0.95 to 1.06]
  

  —

  The proportion of women with blood loss of at least 1000 mL at 1 hour,and up to 2 hours for women who continued to bleed after 1 hour was 1.51% in the carbetocin group and 1.45% in the oxytocin group (relative risk, 1.04;95% CI, 0.87 to 1.25), with the confidence interval crossing the margin of noninferiority*

• *

  Randomized, double-blind, noninferiority trial. 23 study sites, 10 countries. n= 29,645 women. Intramuscular injections of heat-stable carbetocin (at a dose of 100 mcg) was compared with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Primary outcomes: Proportion of women with blood loss of >500 mL or the use of additional uterotonic agents and proportion of women with blood loss of at least 1000 mL, and up to 2 hours for women who continued to bleed after 1 hour. Noninferiority margins for the relative risks of these outcomes were 1.16 and 1.23, respectively.

• DURATOCIN is an analogue of oxytocin

PHARMACOLOGICAL ACTION OF CARBETOCIN^1*

• DURATOCIN selectively binds to oxytocin receptors on the smooth musculature of the uterus
• Binding results in rhythmic contractions of the uterus, increased frequency of existing contractions, and increased uterine tone

• A firm uterine contraction is obtained within 2 minutes, with either intravenous or intramuscular route

• Based on healthy female subjects in the dose range of 400 to 800 mcg
• Recommended DURATOCIN dose is 100 mcg
• DURATOCIN shows a biphasic elimination after intravenous administration with linear pharmacokinetics in the dose range of 400 to 800 mcg.
• Half-life is 33 minutes after IV administration
• Half-life is 55 minutes after IM administration – peak concentrations are reached after 30 minutes

• *	Clinical significance is unknown.

• In a large, randomized, active controlled, double-blind clinical trial, 14,754 subjects received carbetocin (IM) and 14,743 subjects received oxytocin (IM). Carbetocin (100 mcg IM) and oxytocin (10 IU IM) have a similar safety profile in the prevention of PPH following vaginal delivery. Table 1 below summarizes the TEAEs.¹
• Most frequent TEAEs for carbetocin (≥0.2% and <1%) were anemia, abdominal pain, vomiting, pyrexia, post-procedural swelling and postpartum haemorrhage

• The adverse drug reactions observed with carbetocin during the clinical trials were of the same type and frequency as the adverse events observed with oxytocin and placebo when administered after caesarean section under epidural or spinal anesthesia.
• Very common ADRs in clinical trials of elective caesarean section (>1/10): Headache, tremor, hypotension, flushing, nausea, abdominal pain, vomiting, pruritus, feeling of warmth

• *

  A randomized, active controlled, double-blind, parallel group trial was conducted in healthy pregnant women undergoing vaginal delivery to establish the efficacy of carbetocin (IM) in the prevention of postpartum haemorrhage following vaginal delivery. Patients were randomized to receive a single IM of either DURATOCIN 100 mcg IM (n= 14,771) or oxytocin 10 IU IM (n=14,768). Primary endpoint: blood loss of ≥500 mL or use of additional uterotonics

DURATOCIN IV VS. OXYTOCIN IV
Ferring DURATOCIN (100 mcg IV+Ringer’s lactate solution 10 mL injected directly into the vein over 2 min) showed significantly better outcomes vs. emergency caesarean with oxytocin (20 IU diluted in 1000 mL of Ringer’s lactate solution, administered intravenously at a rate of 125 mL/hr)

IN PREGNANT WOMEN UNDERGOING EMERGENCY CAESAREAN

• 2% vs. 13% oxytocin in postpartum hemorrhage (p=0.03)
• Estimated blood loss 689 ± 580 mL vs. 1027 ± 659 mL oxytocin (p=0.002)
• 0 vs. 16% oxytocin in need for transfusion (p=0.04)
• 2% vs. 71% oxytocin in patients who needed additional uterotonics (p=0.002)

• ‡

  A randomised, active-controlled, double-blind, parallel-group trial compared the effectiveness of DURATOCIN 100 mcg IV (n=188) and oxytocin 5 IU IV< (n= 189) in elective and emergency caesarean section, administered after caesarean section for prevention of postpartum haemorrhage (PPH). Primary endpoint: Incidence of need for additional oxytocin intervention1

• El-Behery et al. reported a significant difference in the amount of estimated blood loss and in the incidence of primary postpartum haemorrhage
  (≥ 1000 mL) in both groups (carbetocin 100 mcg IV; oxytocin= 20 IU, 8 hour IV infusion).^5†§ 

  • —	Incidence of blood loss in the carbetocin group was 689 ± 580 mL vs. 1027 ± 659 mLs for the oxytocin group (p=0.002)
    —	Incidence of PPH in carbetocin group was 2/90 or 2.2% vs. 12/90 or 13.33% for the oxytocin group (p=0.03)

• Haemoglobin levels before and 24-h postpartum were similar
• Mean hemoglobin decrease g/dL: carbetocin=1.74 vs. oxytocin=0.94 (p=0.03)
• 2.22% of patients in the carbetocin group versus 71.11% of patients in the oxytocin group needed additional uterotonics (p=0.002)
• Uterine contractility was better in the carbetocin group at 2 and 12 hours postpartum (p<0.05)

• †	The primary outcome measure was major primary postpartum hemorrhage defined as blood loss ≥1000 mL within 24 hours of delivery as per the definition of PPH by the World Health Organization
  §	A randomized, active-controlled, double-blind, double-dummy, parallel-group trial of obese (BMI>30), nulliparous pregnant women undergoing emergency caesarean. DURATOCIN 100 mcg IV (n=90), oxytocin 20 IU 8 h IV infusion (n= 90). Primary endpoint: blood loss ≥1000 mL within 24 h of delivery. Mean hemoglobin decrease g/dL: carbetocin=1.74 vs. oxytocin= 0.94

• Room temperature stable DURATOCIN can be administered in vaginal (IM or IV) or caesarean section (IV) deliveries¹

IM OR IV ADMINISTRATION IN VAGINAL DELIVERY¹

• A single dose of 100 mcg (1 mL) of DURATOCIN is given by intramuscular injection or slowly over 1 minute by intravenous bolus injection, under adequate medical supervision
• DURATOCIN must be given as soon as possible after delivery of the infant, preferably before the delivery of the placenta
• No further doses of DURATOCIN should be given

IV ADMINISTRATION IN CAESAREAN SECTION¹

• A single intravenous dose of 100 mcg (1 mL) of DURATOCIN is given by bolus injection, slowly over 1 minute, only when delivery of the infant has been completed by caesarean section under epidural or spinal anaesthesia
• DURATOCIN can be given before or after delivery of the placenta
• No further doses of DURATOCIN should be given

• Single 100 mcg dose for vaginal (IM or IV) or caesarean delivery (IV)¹
• Single IM or IV 100 mcg dose is administered by bolus injection, slowly over 1 minute for vaginal delivery
• Shown to reduce the need for additional uterotonic administration in pregnant women with an increased risk of postpartum haemorrhage undergoing C-section¹
  – 2% of carbetocin subjects needed additional uterotonics vs. 71% of oxytocin subjects (p=0.0002)^‡

• ‡

  A randomized, active-controlled, double-blind, parallel-group trial compared the effectiveness of DURATOCIN 100 mcg IV (n=188) and oxytocin 5 IU IV (n=189) in elective and emergency caesarean section, administered after caesarean section for prevention of postpartum haemorrhage (PPH). Primary endpoint: Incidence of need for additional oxytocin intervention1

DEMONSTRATED EFFICACY IN PREVENTING POSTPARTUM HEMORRHAGE BY CONTROLLING UTERINE ATONY¹

• DURATOCIN IM in vaginal deliveries was shown to be at least as effective as oxytocin IM in blood loss of at least 500 mL or the need for additional uterotonic agents^1*
• Uterine contractility was shown to be superior with DURATOCIN IV vs. oxytocin at 2 hours and 12 hours after emergency caesarean section (p<0.05)^1*

• *

  Double-blind, randomized-controlled trial. n=180 pregnant women with BMI>30 randomized to receive oxytocin (2 ampoules; 20 IU) or DURATOCIN (100 mcg) by IV, during caesarean surgery. Primary outcome: major primary PPH ≥1000 mL within 24 hours of delivery. Secondary outcomes: hemoglobin and hematocrit changes pre and post-delivery, use of further ecobolics, uterine tone and adverse effects. Study results: Major primary PPH: DURATOCIN = 2.22% vs. oxytocin = 13.33%; p=0.03. Postpartum hemoglobin level: DURATOCIN = 11.4 ± 1.76 g/dL vs. oxytocin = 10.8 ± 1.68 g/dL; p=0.09. Soft uterine tone: DURATOCIN = 2.22% vs. oxytocin=15.55%; p<0.05. Need for additional uterotonics: DURATOCIN = 2.22% vs. oxytocin= 71.11%; p<0.005