Duratocin Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Duratocin Injection - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Australia
Condition: Postpartum Bleeding
Class: Uterotonic agents
Form: Liquid solution, Intramuscular (IM), Intravenous (IV)
Ingredients: Carbetocin, methionine, succinic acid, mannitol, sodium hydroxide, water for injections.

Pharmaceutical Information

Drug Substance

Proper NameCarbetocin (INN)
Chemical Name1-desamino-1-monocarba-2-(0-methyl)-tyrosine oxytocin
Other Names[2-0-methyltyrosine]-1-deaminocarba-1-oxytocin
[6,1,B-deaminocystathionine,2-0-methyl-tyrosine-oxytocin]
[tyr(me)2]-deamino-1-carba-oxytocin
Chemical Structure


Molecular Weight988.1
Molecular FormulaC45H69N11O12S
Description Carbetocin is a white, fluffy lyophilized powder, soluble in water, ethanol, methanol and acetic acid. Carbetocin is insoluble in ether and petroleum ether. The pH of carbetocin is 3.9.

Composition

Each ampoule contains 100 μg (0.1 mg) of carbetocin, 9 mg sodium chloride, glacial acetic acid (6-14 μg) and water for injection q.s. to 1 mL. Ampoules are clear glass with a white identification ring and a blue dot indicating the cut area.

Stability and Storage Recommendations

DURATOCIN (carbetocin injection) must be stored at refrigerator temperature (2-8°C). DURATOCIN should not be frozen. Once the ampoule has been opened, the product should be used immediately.

Availability of Dosage Forms

DURATOCIN (carbetocin injection) is available in 1 mL ampoules. Each ampoule contains 100 μg carbetocin. Boxes contain 5 ampoules each.

Instructions for Opening Ampoules

  1. Hold ampoule with blue dot pointing upwards. Shake or tap ampoule to empty the tip.
  2. With blue dot pointing upwards, snap off tip by forcing it downwards.

Pharmacology

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.

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 μg 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 μg carbetocin, respectively. Dose levels of 50 μg and 100 μg carbetocin produced a tetanic uterine contraction. Results of the above trial are seen in the following table.

Breakdown of Patients by the Number of Doses Required to Produce Tetany
Increment
size (μg)
Case
No.
No. of
increments
administered
Total
dose (μg)
Tetantic
dose (μg)
Efficacy of a
single dose
100511001001/1(100%)
501150501/1(100%)
102220206/10 (60%)
3440No tetanya
444030
622010
733010
8110No tetanyb
911010
1011010
1411010
1511010
211510100/5 (0%)
125108
13488
16612No tetanyc
17510No tetanyd

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 distribution and elimination half-lives of carbetocin in non-pregnant women were found to be 5.5 ± 1.6 minutes and 41 ± 11.9 minutes respectively after a 400 μg intravenous dose, indicating a lack of dose-dependency for this parameter. The clearance of carbetocin from the body (both total and renal), and the volume of distribution do not appear to be dose dependent, whereas Cmax and AUC0-4 show proportional changes with increasing dose.

Approximately 0.7% of the carbetocin dose is eliminated in the unchanged form by the kidney, indicating that carbetocin, like oxytocin, is eliminated primarily by non-renal routes.

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

Summary of Pharmacokinetic Parameters
Intravenous Injection
Parameter400 μg IV800 μg IV
AUC (0 to 4)
(μg*min/L)
Mean749.2±131.01,370.4±214.9
Range539.5-916.91,148-1,733
Clt
(L/min)
Mean0.549±0.1050.595±0.089
Range0.436-0.7410.462-0.696
Clr
(L/min)
Mean0.004±0.0020.004±0.002
Range0.002-0.0070.002-0.007
Clnr
(L/min)
Mean0.545±0.1030.591±0.089
Range0.433-0.7350.458-0.692
Vc
(L)
Mean9.27±2.988.38±1.78
Range5.2-13.66.4-11.3
Alpha HL
(min)
Mean5.54±1.66.05±1.15
Range3.3-7.85.1-8.2
Beta HL
(min)
Mean41.0±11.942.7±10.6
Range28.7-59.239.3-49.4
Cmax
(μg/L)
Mean--
Range
Tmax
(min)
Mean--
Range
F
(%)
Mean--
Range
Ae
(%)
Mean0.70±0.300.68±0.30
Range0.36-1.130.42-1.20

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; Cmax = peak concentration; Tmax = time to peak concentration; F= percent bioavailability of intramuscular carbetocin; Ae =percent carbetocin.

Clinical Trials

Two large double blind trials were conducted using carbetocin. The first trial evaluated the safety and efficacy of carbetocin versus placebo for control of bleeding after cesarean section. This multicentre trial included 122 patients. Efficacy was determined as the requirement for intervention with additional oxytocic therapy following test drug administration.

When given as a single bolus intravenous dose of 100 μg after delivery of the infant at elective cesarean section done under epidural, carbetocin was found to be significantly more effective than placebo in preventing uterine atony and excessive bleeding with only 13% of patients requiring intervention with further oxytocic therapy compared to 72% of patients in the placebo group (p=0.001).

The second double-blind trial compared a single intravenous dose of 100 μg carbetocin to an 8-hour oxytocin infusion after elective cesarean section done under epidural or spinal anesthesia. The primary objective was to compare the safety and efficacy of the two treatments in maintaining adequate uterine contraction after cesarean section. The primary efficacy variable was the incidence rate of the need for further oxytocic therapy for 48 hours after delivery. Carbetocin was associated with lower incidence of "need for additional oxytocic intervention" when compared to oxytocin: such intervention occurred in 5% of patients receiving carbetocin compared to 10% of patients administered oxytocin. Carbetocin was associated with a significantly longer time to intervention when compared to oxytocin: 2.03 versus 0.18 hours respectively (medians).

The dose-response relationship of carbetocin and uterine contraction was evaluated in a clinical trial involving 18 patients. 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 μg intravenous injection was capable of maintaining contraction after cesarean section.

In another trial carbetocin was compared to oxytocin for their ability to reduce intraoperative blood loss during cesarean section. A single 100 μg injection of carbetocin was compared to oxytocin (total dose 32.5 IU).

It was found that a single intravenous bolus injection of carbetocin was at least as effective as 16 hours of continuous oxytocin infusion, in terms of efficacy in maintaining uterine contraction after cesarean section, and in preventing excessive intraoperative blood loss following cesarean delivery. This study confirmed the ability of a 100 μg intravenous dose of carbetocin to maintain adequate uterine tone after cesarean section.

Carbetocin also appeared to accelerate the initial stages of uterine involution, associated with the return of the uterus to the non-pregnant size and position.

Toxicology

In acute toxicology studies, the LD50 was estimated at 10 mg/kg in an intravenous rat study. Marked clinical signs (lethargy, hunched posture, piloerection, rapid breathing and uncoordinated movement) were noted for all animals. Using this LD50, the corresponding dose for a 100 g rat would be 1,000 μg, which is ten times the dose used in humans.

Four groups of 20 rats were given carbetocin intravenous at doses of up to 1.0 mg/kg/day for 28 days. There were no deaths or clinical signs attributable to treatment.

Sixteen female beagles were given carbetocin by intravenous injection daily for 28 days at doses of up to 1.0 mg/kg/day. There were no deaths or clinical signs attributable to treatment. No treatment related changes in hematology, clinical chemistry or urinalysis occurred.

Carbetocin was found to be devoid of mutagenic activity in a battery of mutagenicity tests. Carcinogenicity studies have not been performed.

Reproduction and teratology studies have not been performed since the drug is intended for a single administration immediately after delivery.