Zuellig Pharma
Full Prescribing Info
Atosiban acetate.
Each mL of solution for injection and infusion contains atosiban free base 7.5 mg as atosiban acetate. Each vial of solution for injection and infusion contains atosiban 6.75 and 37.5 mg, respectively.
Tractocile also contains the following inactive ingredients: Mannitol, hydrochloric acid 1M and water for injections.
Pharmacology: Atosiban, a synthetic peptide ([Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin), is a competitive antagonist of human oxytocin at receptor level. In rats and guinea pigs, atosiban was shown to bind to oxytocin receptors, to decrease the frequency of contractions and the tone of the uterine musculature, resulting in a suppression of uterine contractions. Atosiban was also shown to bind to the vasopressin receptor, thus inhibiting the effect of vasopressin.
In animals, atosiban did not exhibit cardiovascular effects.
In human pre-term labour, atosiban at the recommended dosage antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 min to achieve stable uterine quiescence (≤4 contractions/hr) for 12 hrs.
Phase III clinical trials (CAP-001 studies) include data from 742 women who were diagnosed with pre-term labour at 23-33 weeks of gestation and were randomised to receive either Tractocile or β-agonist (dose-titrated).
Primary Endpoint: The primary efficacy outcome was the proportion of women remaining undelivered and not requiring alternative tocolysis within 7 days of treatment initiation. The data show that 59.6% (n=201) and 47.7% (n=163) of atosiban- and β-agonist-treated women (p=0.0004), respectively, were undelivered and did not require alternative tocolysis within 7 days of starting treatment. Most of the treatment failures in CAP-001 were caused by poor tolerability. Treatment failures caused by insufficient efficacy were significantly (p=0.0003) more frequent in atosiban (n=48, 14.2%) than in the β-agonist-treated women (n=20, 5.8%).
In the CAP-001 studies, the probability of remaining undelivered and not requiring alternative tocolytics within 7 days of treatment initiation was similar for atosiban and β-mimetic treated women at gestational age of 24-28 weeks. However, this finding is based on a very small sample (n=129 patients).
Secondary Endpoints: Secondary efficacy parameters included the proportion of women remaining undelivered within 48 hrs of treatment initiation. There was no difference between the atosiban and β-mimetic groups with regard to this parameter. Mean (SD) gestational age at delivery was the same in the 2 groups: 35.6 (3.9) and 35.3 (4.2) weeks for the atosiban and β-agonist groups, respectively (p=0.37).
Admission to a neonatal intensive care unit (NICU) was similar for both treatment groups (approximately 30%), as was length of stay and ventilation therapy. Mean (SD) birth weight was 2491 (813) g in the atosiban group and 2461 (831) g in the β-agonist group (p=0.58).
Foetal and maternal outcome did apparently not differ between the atosiban and the β-agonist group, but the clinical studies were not powered enough to rule out a possible difference. Of the 361 women who received Tractocile treatment in the phase III studies, 73 received at least 1 re-treatment, 8 received at least 2 re-treatments and 2 received 3 re-treatments.
As the safety and efficacy of Tractocile in women with a gestational age of <24 completed weeks has not been established in controlled randomised studies, the treatment of this patient group with Tractocile is not recommended.
In a placebo-controlled study, foetal/infant deaths were 5/295 (1.7%) in the placebo group and 15/288 (5.2%) in the Tractocile group, of which 2 occurred at 5 and 8 months of age. Eleven out of the 15 deaths in the Tractocile group occurred in pregnancies with a gestational age of 20-24 weeks, although in this subgroup, patient distribution was unequal (19 women on Tractocile, 4 on placebo). For women with a gestational age >24 weeks, there was no difference in mortality rate (1.7% in the placebo group and 1.5% in the Tractocile group).
Pharmacokinetics: In healthy nonpregnant subjects receiving Tractocile infusions (10-300 mcg/min over 12 hrs), the steady-state plasma concentrations increased proportionally to the dose. The clearance, volume of distribution and half-life were found to be independent of the dose.
In women in pre-term labour receiving Tractocile by infusion (300 mcg/min for 6-12 hrs), steady-state plasma concentrations were reached within 1 hr following the start of the infusion (mean 442±73 ng/mL, range 298-533 ng/mL). Following completion of the infusion, plasma concentration rapidly declined with an initial (tα) and terminal (tβ) half-life of 0.21±0.01 and 1.7±0.3 hrs, respectively. Mean value for clearance was 41.8±8.2 l/h. Mean value of volume of distribution was 18.3±6.8 L.
Plasma protein binding of atosiban is 46-48% in pregnant women. It is not known whether the free fraction in the maternal and foetal compartments differs substantially. Atosiban does not partition into red blood cells.
Atosiban passes the placenta. Following an infusion of 300 mcg/min in healthy pregnant women at term, the foetal/maternal atosiban concentration ratio was 0.12.
Two metabolites were identified in the plasma and urine from human subjects. The ratios of the main metabolite M1 (des-(Orn8,Gly-NH29)-[Mpa1,D-Tyr(Et)2, Thr4]-oxytocin) to atosiban concentrations in plasma were 1.4 and 2.8 at the 2nd hr and at the end of the infusion, respectively. It is not known whether M1 accumulates in tissues. Atosiban is found in only small quantities in the urine, its urinary concentration is about 50 times lower than that of M1. The proportion of atosiban eliminated in faeces is not known. Main metabolite M1 is apparently as potent as the parent compound in inhibiting oxytocin-induced uterine contractions in vitro. Metabolite M1 is excreted in milk. There is no experience with Tractocile treatment in patients with impaired function of the liver or kidneys.
It is unlikely that atosiban inhibits hepatic cytochrome P-450 isoforms in humans.
Toxicology: Preclinical Safety Data: No systemic toxic effects were observed during the 2-week IV toxicity studies (in rats and dogs) at doses which are approximately 10 times higher than the human therapeutic dose, and during the 3-months toxicity studies in rats and dogs (up to 20 mg/kg/day SC). The highest atosiban SC dose not producing any adverse effects was approximately 2 times the therapeutic human dose.
Reproduction toxicity studies showed no effects on mothers or offspring. The exposure of the rat foetus was approximately 4 times that received by the human foetus during IV infusions in women. Animal studies have shown inhibition of lactation as expected from the inhibition of action of oxytocin. Atosiban was neither oncogenic nor mutagenic in in vitro and in vivo tests.
For the delay of imminent pre-term birth in pregnant women with: Regular uterine contractions of at least 30-sec duration at a rate of ≥4/30 min; a cervical dilation of 1-3 cm (0-3 for nulliparas) and effacement of ≥50%; age ≥18 years; a gestational age from 28 until 33 completed weeks; a normal foetal heart rate.
Dosage/Direction for Use
Treatment with Tractocile should be initiated and maintained by a physician experienced in the treatment of pre-term labour.
Tractocile is administered IV in 3 successive stages: An initial bolus dose (6.75 mg), performed with Tractocile 7.5 mg/mL solution for slow IV infusion for 1 min, followed by a continuous high-dose infusion [loading infusion 300 mcg/min (or 18 mg/hr)] of Tractocile 7.5 mg/mL concentrate solution for infusion during 3 hrs, followed by a lower dose of Tractocile 7.5 mg/mL concentrate solution for infusion [subsequent infusion 100 mcg/min (6 mg/hr)] up to 45 hrs.
The duration of the treatment should not exceed 48 hrs. The total dose given during a full course of Tractocile therapy should preferably not exceed 330 mg of the active substance.
IV therapy using the initial bolus injection should be started as soon as possible after diagnosis of pre-term labour. Once the bolus has been injected, proceed with the infusion. In the case of persistence of uterine contractions during treatment with Tractocile, alternative therapy should be considered.
There is no data available regarding the need for dose adjustments in patients with renal or liver insufficiency.
The following table shows the full posology of the bolus injection followed by the infusion: See Table.

Click on icon to see table/diagram/image

Re-treatment: In case a re-treatment with Tractocile is needed, it should also commence with a bolus injection of Tractocile 7.5 mg/mL, solution for injection followed by infusion with Tractocile 7.5 mg/mL concentrate solution for infusion.
Preparation of Solutions: IV Injection: Initially, withdraw 0.9 mL of a 0.9 mL labelled vial of Tractocile 7.5 mg/mL, solution for injection and administer slowly as an IV bolus dose over 1 min, under adequate medical supervision in an obstetric unit. The Tractocile 7.5 mg/mL solution for injection should be used immediately.
IV Infusion: For IV infusion, following the bolus dose, Tractocile 7.5 mg/mL concentrate solution for infusion should be diluted in 1 of the following solutions: 0.9% w/v NaCl; Ringer's lactate solution; 5% w/v glucose solution.
Withdraw 10 mL solution from a 100-mL infusion bag and discard. Replace it by 10 mL Tractocile 7.5 mg/mL concentrate solution for infusion from two 5-mL vials to obtain a concentration of 75 mg atosiban in 100 mL. The loading infusion is given by infusing 24 mL/hr (ie, 18 mg/hr) of the previously prepared solution over the 3-hr period under adequate medical supervision in an obstetric unit. After 3 hrs, the infusion rate is reduced to 8 mL/hr.
Prepare new 100 mL bags in the same way as described to allow the infusion to be continued. If an infusion bag with a different volume is used, a proportional calculation should be made for the preparation. To achieve accurate dosing, a controlled infusion device is recommended to adjust the rate of flow in drops/min. An IV microdrip chamber can provide a convenient range of infusion rates within the recommended dose levels for Tractocile.
Few cases of Tractocile overdosing were reported. They occurred without any specific signs or symptoms. There is no known specific treatment in case of an overdose.
Tractocile should not be used in the following conditions: Gestational age below 28 or over 33 completed weeks; premature rupture of the membranes >30 weeks of gestation; intrauterine growth retardation and abnormal foetal heart rate; antepartum uterine haemorrhage requiring immediate delivery; eclampsia and severe pre-eclampsia requiring delivery; intrauterine foetal death; suspected intrauterine infection; placenta praevia; abruptio placenta; any other conditions of the mother or foetus, in which continuation of pregnancy is hazardous; known hypersensitivity to atosiban or any of the excipients of Tractocile.
Special Precautions
When Tractocile is used in patients in whom premature rupture of membranes cannot be excluded, the benefits of delaying delivery should be balanced against the potential risk of chorioamnionitis.
There is no experience with Tractocile treatment in patients with impaired function of the liver or kidneys.
Tractocile has not been used in patients with an abnormal placental site.
There is only limited clinical experience in the use of Tractocile in multiple pregnancies or the gestational age group between 24 and 27 weeks, because of the small number of patients treated. The benefit of Tractocile in these subgroups is therefore uncertain.
Re-treatment with Tractocile is possible, but there is only limited clinical experience available with multiple re-treatments, up to 3 re-treatments. In case of intrauterine growth retardation, the decision to continue or reinitiate the administration of Tractocile depends on the assessment of foetal maturity. Monitoring of uterine contractions and foetal heart rate during administration of Tractocile and in case of persistent uterine contractions should be considered.
As an antagonist of oxytocin, atosiban may theoretically facilitate uterine relaxation and postpartum bleeding therefore, blood loss after delivery should be monitored. However, inadequate uterus contraction postpartum was not observed during the clinical trials.
Effects on the Ability to Drive or Operate Machinery: Not applicable.
Use in pregnancy & lactation: Tractocile should only be used when pre-term labour has been diagnosed between 28 and 33 completed weeks of gestation. Embryotoxicity studies have not shown toxic effects of atosiban.
In Tractocile clinical trials no effects were observed on lactation. Small amounts of atosiban have been shown to pass from plasma into the breast milk of lactating women.
Use In Pregnancy & Lactation
Tractocile should only be used when pre-term labour has been diagnosed between 28 and 33 completed weeks of gestation. Embryotoxicity studies have not shown toxic effects of atosiban.
In Tractocile clinical trials no effects were observed on lactation. Small amounts of atosiban have been shown to pass from plasma into the breast milk of lactating women.
Adverse Reactions
Possible undesirable effects of atosiban were described for the mother during the use of Tractocile in clinical trials. The observed undesirable effects were generally of a mild severity. In total 48% of the patients treated with Tractocile experienced undesirable effects.
For the newborn, the clinical trials did not reveal any specific undesirable effects of atosiban. The infant adverse events were in the range of normal variation and were comparable with both placebo and β-mimetic group incidences. The undesirable effects in women were the following: Very Common (>10%): Nausea.
Common (1-10%): Central and Peripheral Nervous System Disorders: Headache, dizziness.
Body as a Whole: General Disorders: Hot flushes.
Gastrointestinal System Disorders: Vomiting.
Cardiovascular Disorders: Tachycardia, hypotension.
Application Site Disorders: Injection site reaction.
Metabolic and Nutritional Disorders: Hyperglycaemia.
Uncommon (0.1-1%): Body as a Whole: General Disorders: Fever.
Psychiatric Disorders: Insomnia.
Skin and Appendages Disorders: Pruritis, Rash.
Rare (<0.1%): Incidental cases of uterine haemorrhage/uterine atony were reported. The frequency did not exceed that of the control groups in clinical trials. One case of allergic reaction was reported, which was considered to be probably related to atosiban.
Drug Interactions
It is unlikely that atosiban is involved in cytochrome P-450 mediated drug-drug interactions, as in vitro investigations have shown that atosiban is not a substrate for the cytochrome P-450 system and does not inhibit the drug metabolising cytochrome P-450 enzymes.
Interaction studies were performed in healthy, female volunteers with betamethasone and labetalol. No clinically relevant interaction was observed between Tractocile and betamethasone. When Tractocile and labetalol were co-administered, Cmax of labetalol was decreased by 36% and Tmax increased by 45 min. However, the extent of labetalol bioavailability in terms of AUC did not change. The interaction observed has no clinical relevance. Labetalol had no effect on Tractocile pharmacokinetics.
No interaction study has been performed with antibiotics, ergot alkaloids, and antihypertensive agents other than labetalol.
Caution For Usage
Once the vial has been opened, Tractocile must be used immediately. The vials should be inspected visually for particulate matter and discoloration prior to administration.
In the absence of incompatibility studies, Tractocile should not be mixed with other medicinal products. If other medicinal products need to be given IV at the same time, the IV cannula can be shared or another site of IV administration can be used. This permits the continued independent control of the rate of infusion.
Storage: Store at 2-8°C.
Shelf-Life: 2 years.
ATC Classification
G02CX01 - atosiban ; Belongs to the class of other gynecologicals. Used to inhibit uncomplicated premature labour between 24 and 33 weeks of gestation.
IV inj vial 7.5 mg/mL x 0.9 mL x 1's. IV infusion vial 7.5 mg/mL x 5 mL x 1's.
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