DURATOCIN Solution for injection Ref.[27961] Active ingredients: Carbetocin

DURATOCIN (carbetocin injection) is a long-acting synthetic nonapeptide analogue of oxytocin with agonist properties. It can be administered intravenously as a single dose immediately following delivery by cesarean section under epidural or spinal anesthesia, to prevent uterine atony and postpartum hemorrhage.

The clinical and pharmacological properties of carbetocin are similar to those of naturally occurring oxytocin, another posterior pituitary hormone. Like oxytocin, carbetocin selectively binds to oxytocin receptors present on the smooth musculature of the uterus, resulting in rhythmic contractions of the uterus, increased frequency of existing contractions, and increased uterine tone. The oxytocin receptor content of the uterus is very low in the non-pregnant state, and increases during pregnancy, reaching a peak at the time of delivery. Therefore carbetocin has no effect on the non-pregnant uterus, and has a potent uterotonic effect on the pregnant and immediate postpartum uterus.

The onset of uterine contraction following carbetocin administration by either the intravenous or intramuscular route is rapid, with a firm contraction being obtained within 2 minutes. The total duration of action of a single intravenous injection of carbetocin on uterine activity is about one hour suggesting that carbetocin may act long enough to prevent postpartum hemorrhage in the immediate postpartum period. In comparison to oxytocin, carbetocin induces a prolonged uterine response when administered postpartum, in terms of both amplitude and frequency of contractions. Carbetocin, when administered immediately postpartum as a single intravenous bolus injection of 100 mcg to women delivered by cesarean section under epidural or spinal anesthesia, was found to be significantly more effective than placebo in preventing uterine atony and minimizing uterine bleeding.

Carbetocin administration also appears to enhance uterine involution in the early postpartum period.

Pharmacodynamics

In vivo studies in rats demonstrated that carbetocin has a uterotonic effect comparable to oxytocin. The maximum intensity is lower but the duration is longer.

The dose-response relationship of carbetocin and uterine contraction was evaluated in an openlabel clinical trial involving 18 healthy pregnant women undergoing elective cesarean section under epidural anesthesia (CLN 6.3.5). Here the intravenous dose of carbetocin required to produce sustained tetanic contraction after cesarean section was determined. “Minimally effectiveness dose” was determined, and was defined as the dose that produces adequate uterine contraction in 100% of patients. A single 100 mcg intravenous injection was capable of maintaining contraction after cesarean section.12

An exploratory study in women after normal vaginal delivery was undertaken to determine the intravenous dose of carbetocin required to produce a sustained contraction of the postpartum uterus. Seventeen (17) women received a single intravenous dose of 8-100 mcg carbetocin on day 1 to 2 postpartum. In total, 14 women achieved tetanic uterine contraction while no response was observed in 3 women after 10, 12 and 40 mcg carbetocin, respectively. Dose levels of 50 mcg and 100 mcg carbetocin produced a tetanic uterine contraction. Results of the above trial are seen in the following table.

Table 3. Breakdown of Patients by Number of Doses Required to Produce Tetany:

^a Record not analyzable. Patient reported cramping starting 2 minutes after first injection which continued for about 5 minutes after injection of last dose.
^b Record not analyzable. Patient reported cramping starting 2 minutes after first injection.
^c Record not analyzable. Patient reported no cramping.
^d Record not analyzable. Patient reported definite contractions starting at 1 min. 40 sec., and lasting for 60 min. after injection.

The onset of uterine activity after intravenous carbetocin is rapid, occurring within 1.2 + 0.5 minutes. Total duration of a single injection of intravenous carbetocin on uterine activity is about one hour.

Pharmacokinetics

The clearance of carbetocin from the body (both total and renal), the volume of distribution, and the distribution and elimination half-life do not appear to be dose dependent, whereas C_max and AUC0-4 show proportional changes with increasing dose.

Carbetocin shows a biphasic elimination after intravenous administration with linear pharmacokinetics in the dose range of 400 to 800 micrograms. The terminal elimination half-life is approximately 40 minutes. Renal clearance of the unchanged form is low, with <1% of the injected dose excreted unchanged by the kidney, indicating that carbetocin, like oxytocin, is eliminated mainly by non-renal routes.

The pharmacokinetic parameters of intravenous carbetocin are seen in the following table.

Table 4. Summary of Pharmacokinetic Parameters:

AUC = area under the curve; Clt = total body clearance; Clr = renal clearance; Clnr = nonrenal clearance; Vc = volume of the central compartment; alpha-HL = distribution half-life; beta-HL = elimination half-life; C_max = peak concentration; Tmax = time to peak concentration; F= percent bioavailability of intramuscular carbetocin; Ae =percent carbetocin.

Small amounts of carbetocin are transferred into human breast milk. In 5 healthy nursing mothers, plasma carbetocin concentrations peaked at 1035 ± 218 pg/ml between 15 and 30 min of administering the drug. Peak concentrations in milk at 120 min were approximately 56 times lower than peak concentrations in plasma.