Few cases of Трактоцил overdosing were reported, they occurred without any specific signs or symptoms. There is no known specific treatment in case of an overdose.
Трактоцил must not be used in the following conditions:
- Gestational age below 24 or over 33 completed weeks
- Premature rupture of the membranes >30 weeks of gestation
- 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
Possible adverse reactions of Трактоцил were described for the mother during the use of Трактоцил in clinical trials. In total 48% of the patients treated with Трактоцил experienced adverse reactions during the clinical trials. The observed adverse reactions were generally of a mild severity. The most commonly reported adverse reaction in the mother is nausea (14 %).
For the newborn, the clinical trials did not reveal any specific adverse reactions of Трактоцил. The infant adverse reactions were in the range of normal variation and were comparable with both placebo and beta-mimetic group incidences.
The frequency of adverse reactions listed below is defined using the following convention: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| MedDRA System Organ Class (SOC) | Very common | Common | Uncommon | Rare |
| Immune system disorders | Allergic reaction | |||
| Metabolism and nutrition disorders | Hyperglycaemia | |||
| Psychiatric disorder | Insomnia | |||
| Nervous system disorders | Headache, Dizziness | |||
| Cardiac disorders | Tachycardia | |||
| Vascular disorders | Hypotension, Hot flush | |||
| Gastrointestinal disorders | Nausea | Vomiting | ||
| Skin and subcutaneous tissue disorders | Pruritis, Rash | |||
| Reproductive system and breast disorder | Uterine haemorrhage, uterine atony | |||
| General disorders and administration site conditions | Injection site reaction | Pyrexia |
Post-marketing experience
Respiratory events like dyspnoea and pulmonary oedema, particularly in association with concomitant administration of other medicinal products with tocolytic activity, like calcium antagonists and beta-mimetics, and/or in women with multiple pregnancy, have been reported post-marketing.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.
No systemic toxic effects were observed during the two-week intravenous toxicity studies (in rats and dogs) at doses which are approximately 10 times higher than the human therapeutic dose, and during the three-months toxicity studies in rats and dogs (up to 20 mg/kg/day s.c.). The highest Трактоцил subcutaneous dose not producing any adverse effects was approximately two times the therapeutic human dose.
No studies were performed that covered fertility and early embryonic development. Reproduction toxicity studies, with dosing from implantation up to late stage pregnancy, showed no effects on mothers and fetuses. The exposure of the rat fetus was approximately four times that received by the human fetus during intravenous infusions in women. Animal studies have shown inhibition of lactation as expected from the inhibition of action of oxytocin.
Трактоцил was neither oncogenic nor mutagenic in in vitro and in vivo tests.
Трактоцил is indicated to delay imminent pre-term birth in pregnant adult women with:
- regular uterine contractions of at least 30 seconds duration at a rate of > 4 per 30 minutes
- a cervical dilation of 1 to 3 cm (0-3 for nulliparas) and effacement of > 50%
- a gestational age from 24 until 33 completed weeks
- a normal foetal heart rate
Pharmacotherapeutic group: Other gynecologicals, ATC code: G02CX01
Трактоцил SUN contains Трактоцил (INN), a synthetic peptide ([Mpa1, D-Tyr(Et)2, Thr4,Orn8]-oxytocin) which is a competitive antagonist of human oxytocin at receptor level. In rats and guinea pigs, Трактоцил 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. Трактоцил was also shown to bind to the vasopressin receptor, thus inhibiting the effect of vasopressin. In animals Трактоцил did not exhibit cardiovascular effects.
In human pre-term labour, Трактоцил at the recommended dosage antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following Трактоцил is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence (≤ 4 contractions/hour) for 12 hours.
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 Трактоцил (according to this labelling) 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 Трактоцил- 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 Трактоцил (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 Трактоцил and beta-mimetics 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 h of treatment initiation. There was no difference between the Трактоцил and beta-mimetic groups with regard to this parameter.
Mean (SD) gestational age at delivery was the same in the two groups: 35.6 (3.9) and 35.3 (4.2) weeks for the Трактоцил 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) grams in the Трактоцил group and 2461 (831) grams in the β-agonist group (p=0.58).
Fetal and maternal outcome did apparently not differ between the Трактоцил 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 Трактоцил treatment in the phase III studies, 73 received at least one re-treatment, 8 received at least 2 re-treatments and 2 received 3 re-treatments.
As the safety and efficacy of Трактоцил in women with a gestational age of less than 24 completed weeks has not been established in controlled randomised studies, the treatment of this patient group with Трактоцил is not recommended.
In a placebo-controlled study, fetal/infant deaths were 5/295 (1.7%) in the placebo group and 15/288 (5.2%) in the Трактоцил group, of which two occurred at five and eight months of age. Eleven out of the 15 deaths in the Трактоцил group occurred in pregnancies with a gestational age of 20 to 24 weeks, although in this subgroup patient distribution was unequal (19 women on Трактоцил, 4 on placebo). For women with a gestational age greater than 24 weeks there was no difference in mortality rate (1.7% in the placebo group and 1.5% in the Трактоцил group).
In healthy non-pregnant subjects receiving Трактоцил infusions (10 to 300 micrograms/min over 12 hours), 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.
Absorption
In women in pre-term labour receiving Трактоцил by infusion (300 micrograms/min for 6 to 12 hours), steady state plasma concentrations were reached within one hour following the start of the infusion (mean 442 ± 73 ng/ml, range 298 to 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 hours, respectively. Mean value for clearance was 41.8 ± 8.2 litres/h.
Distribution
Mean value of volume of distribution was 18.3 ± 6.8 litres.
Plasma protein binding of Трактоцил is 46 to 48% in pregnant women. It is not known whether the free fraction in the maternal and fetal compartments differs substantially. Трактоцил does not partition into red blood cells.
Трактоцил passes the placenta. Following an infusion of 300 micrograms/min in healthy pregnant women at term, the fetal/maternal Трактоцил concentration ratio was 0.12.
Biotransformation
Two metabolites were identified in the plasma and urine from human subjects. The ratios of the main metabolite M1 (des-(Orn8, Gly-NH2 9) -29)-[Mpa1, D-Tyr(Et)2, Thr4]-oxytocin) to Трактоцил concentrations in plasma were 1.4 and 2.8 at the second hour and at the end of the infusion respectively. It is not known whether M1 accumulates in tissues.
Elimination
Трактоцил is found in only small quantities in urine, its urinary concentration is about 50 times lower than that of M1. The proportion of Трактоцил eliminated in faeces is not known. The main metabolite M1 is approximately 10 times less potent than Трактоцил in inhibiting oxytocin-induced uterine contractions in vitro. Metabolite M1 is excreted in milk.
Patients with renal or liver impairment
There is no experience with Трактоцил treatment in patients with impaired function of the liver or kidneys. Renal impairment is not likely to warrant a dose adjustment, since only a small extent of Трактоцил is excreted in the urine. In patients with impaired hepatic function, Трактоцил should be used with caution.
It is unlikely that Трактоцил inhibits hepatic cytochrome P450 isoforms in humans.
When Трактоцил 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 Трактоцил treatment in patients with impaired function of the liver or kidneys. Renal impairment is not likely to warrant a dose adjustment, since only a small extent of Трактоцил is excreted in the urine. In patients with impaired hepatic function, Трактоцил should be used with caution.
There is only limited clinical experience in the use of Трактоцил in multiple pregnancies or the gestational age group between 24 and 27 weeks, because of the small number of patients treated. The benefit of Трактоцил in these subgroups is therefore uncertain.
Re-treatment with Трактоцил 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 Трактоцил depends on the assessment of fetal maturity.
Monitoring of uterine contractions and fetal heart rate during administration of Трактоцил and in case of persistent uterine contractions should be considered.
As an antagonist of oxytocin, Трактоцил 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.
Multiple pregnancy and medicinal products with tocolytic activity like calcium channel blockers and beta-mimetics are known to be associated with increased risk of pulmonary oedema. Therefore, Трактоцил should be used with caution in case of multiple pregnancy and/or concomitant administration of other medicinal products with tocolytic activity.
Not relevant.
Posology
Treatment with Трактоцил should be initiated and maintained by a physician experienced in the treatment of pre-term labour.
Трактоцил is administered intravenously in three successive stages: an initial bolus dose (6.75 mg), performed with Трактоцил 6.75 mg/0.9 ml solution for injection, immediately followed by a continuous high dose infusion (loading infusion 300 micrograms/min) of Трактоцил 37.5 mg/5 ml concentrate for solution for infusion during three hours, followed by a lower dose of Трактоцил 37.5 mg/5 ml concentrate for solution for infusion (subsequent infusion 100 micrograms/min) up to 45 hours. The duration of the treatment should not exceed 48 hours. The total dose given during a full course of Трактоцил therapy should preferably not exceed 330.75 mg of Трактоцил.
Intravenous therapy using the initial bolus injection of Трактоцил 6.75 mg/0.9 ml, solution for injection (see Summary of Product Characteristics of this product) 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 Трактоцил, alternative therapy should be considered.
The following table shows the full posology of the bolus injection followed by the infusion:
| Step | Regimen | Infusion rate | Трактоцил dose |
| 1 | 0.9 ml intravenous bolus injection given over 1 minute | Not applicable | 6.75 mg |
| 2 | 3 hours intravenous loading infusion | 24 ml/hour (300 μg/min) | 54 mg |
| 3 | Up to 45 hours subsequent intravenous infusion | 8 ml/hour (100 μg/min) | Up to 270 mg |
Re-treatment
In case a re-treatment with Трактоцил is needed, it should also commence with a bolus injection of Трактоцил 6.75 mg/0.9 ml, solution for injection followed by infusion with Трактоцил 37.5 mg/5 ml, concentrate for solution for infusion.
Patients with renal or hepatic impairment
There is no experience with Трактоцил treatment in patients with impaired function of the liver or kidneys. Renal impairment is not likely to warrant a dose adjustment, since only a small extent of Трактоцил is excreted in the urine. In patients with impaired hepatic function, Трактоцил should be used with caution.
Paediatric population
The safety and efficacy of Трактоцил in pregnant women aged less than 18 years have not been established. No data are available.
Method of administration
The vials should be inspected visually for particulate matter and discoloration prior to administration.
Preparation of the intravenous infusion solution:
For intravenous infusion, following the bolus dose, Трактоцил 37.5 mg/5 ml, concentrate for solution for infusion should be diluted in one of the following solutions:
- sodium chloride 9 mg/ml (0.9%) solution for injection
- 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 Трактоцил 37.5 mg/5 ml concentrate for solution for infusion from two 5 ml vials to obtain a concentration of 75 mg Трактоцил in 100 ml.
The reconstituted product is a clear, colourless solution without particles.
The loading infusion is given by infusing 24 ml/hour (i.e. 18 mg/h) of the above prepared solution over the 3 hour period under adequate medical supervision in an obstetric unit. After three hours the infusion rate is reduced to 8 ml/hour.
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 intravenous microdrip chamber can provide a convenient range of infusion rates within the recommended dose levels for Трактоцил.
If other medicinal products need to be given intravenously at the same time, the intravenous cannula can be shared or another site of intravenous administration can be used. This permits the continued independent control of the rate of infusion.
