Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Oxytocin and analogues
ATC code: H01BB03
The pharmacological and clinical properties of carbetocin are those of a long acting oxytocin agonist.

Like oxytocin, carbetocin selectively binds to oxytocin receptors in the smooth muscle of the uterus, stimulates rhythmic contractions of the uterus, increases the frequency of existing contractions, and raises the tone of the uterus musculature.

On the postpartum uterus, carbetocin is capable of increasing the rate and force of spontaneous uterine contractions. The onset of uterine contraction following carbetocin is rapid after intravenous administration, with a firm contraction being obtained within 2 minutes.

A single 100 micrograms intravenous dose of carbetocin administered after the delivery of the infant is sufficient to maintain adequate uterine contraction that prevents uterine atony and excessive bleeding comparable with an oxytocin infusion lasting for several hours.
Clinical efficacy and safety
The efficacy of carbetocin in the prevention of postpartum haemorrhage due to uterine atony following Caesarean section was established in a randomised, active controlled, double-blind, double dummy, parallel- group trial designed to establish the efficacy and safety of carbetocine compared to oxytocin 25 IU. Six- hundred fifty nine healthy pregnant women undergoing elective Caesarean section under epidural anaesthesia received either carbetocin 100 µg/ml as an IV bolus dose or oxyctocin 25 IU as an 8 h IV infusion.
The results of analysis of the primary endpoint, the need for additional oxytocic intervention, showed that additional oxytocic intervention was required in 15 (5%) of the subjects receiving carbetocin 100 µg IV compared with 32 (10%) of the subjects in the oxytocin 25 IU group (p=0.031).
The efficacy of carbetocin in the prevention of postpartum haemorrhage following vaginal delivery was established in one randomised, active controlled, double-blind trial. In total 29645 subjects were randomised to receive a single intramuscular dose of either carbetocin 100 µg or oxytocin 10 IU. For the primary endpoint of blood loss of ≥500 mL or use of additional uterotonics, similar rates were obtained in both treatment groups (carbetocin: 2135 subjects, 14.47%; oxytocin: 2122 subjects, 14.38%; relative risk [RR] 1.01; 95% CI: 0.95 to 1.06), demonstrating non-inferiority of carbetocin compared with oxytocin with regard to the primary endpoint.
Paediatric population
In the clinical development of carbetocin for prevention of postpartum haemorrhage following vaginal delivery 151 women between 12 and 18 years of age received carbetocin at the recommended dosage of 100 µg and 162 received oxytocin 10 IU. Efficacy and safety was similar for the two treatment arms in these patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The pharmacokinetics of carbetocin have been investigated in healthy female subjects. Carbetocin shows a biphasic elimination after intravenous administration with linear pharmacokinetics in the dose range of 400 to 800 micrograms. The median terminal elimination half-life is 33 minutes after intravenous administration.
and 55 minutes after intramuscular administration. After intramuscular administration, peak concentrations are reached after 30 minutes and the mean bioavailability is 77%. The mean volume of distribution at pseudo-equilibrium (Vz) is 22 L. Renal clearance of the unchanged form is low, with <1% of the injected dose excreted unchanged by the kidney.
After intramuscular administration of 70 µg carbetocin inn 5 healthy nursing mothers, carbetocin 
concentrations were detectable in milk samples. Mean peak concentrations in milk were below 20 pg/mL, which was approximately 56 times lower than in plasma at 120 min.