Tractocile

Tractocile

atosiban

Manufacturer:

Ferring

Distributor:

DCH Auriga - Universal
/
Four Star
Full Prescribing Info
Contents
Atosiban.
Description
Each 7.5 mg/mL vial of solution for injection and solution for infusion contains atosiban acetate equivalent to atosiban 6.75 mg in 0.9 mL and 37.5 mg in 5 mL, respectively.
Tractocile also contains the following as excipients: Mannitol, hydrochloric acid 1 M and water for injections.
Action
Pharmacotherapeutic Group: Other gynecologicals. ATC Code: G02CX01.
Pharmacology: Pharmacodynamics: Tractocile contains atosiban (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, 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 uterine 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) included data from 742 women who were diagnosed with pre-term labour at 23-33 weeks of gestation and were randomised to receive either atosiban (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 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 tocolysis within 7 days of treatment initiation was similar for atosiban and β-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 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 (aproximately 30%), as was length of stay and ventilation therapy. Mean (SD) birth weight was 2,491 (813) g in the atosiban group and 2,461 (831) g in the β-agonist group (p=0.58).
Fetal 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 atosiban 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 (see Precautions).
As the safety and efficacy of atosiban 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 atosiban is not recommended (see Contraindications).
In a placebo-controlled study, fetal/infant deaths were 5/295 (1.7%) in the placebo group and 15/288 (5.2%) in the atosiban group, of which 2 occurred at 5 and 8 months of age. Eleven (11) out of the 15 deaths in the atosiban group occurred in pregnancies exposed to atosiban at a gestational age of 20-24 weeks, although in this subgroup, patient distribution was unequal (19 women on atosiban, 4 on placebo). For women exposed at a gestational age >24 weeks, there was no difference in mortality rate (1.7% in the placebo group and 1.5% on the atosiban group).
Pharmacokinetics: In healthy non-pregnant subjects receiving atosiban 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 (t½) were found to be independent of the dose.
In women in pre-term labour receiving atosiban by infusion (300 mcg/min for 6-12 hrs), steady-state plasma concentrations were reached within 1 hr following the start of 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) t½ of 0.21±0.01 and 1.7±0.3 hrs, respectively. Mean value for clearance was 41.8±8.2 L/hr. 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 fetal compartments differ 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 fetal/maternal atosiban concentration ratio was 0.12.
Two (2) metabolites were identified in the plasma and urine from human subjects. The ratios of the main metabolite M1 [des-(Orn8, Gly-NH29)-[Mpa1, D-Tyre(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 in not known. The main metabolite M1 is approximately 10 times less potent than atosiban in inhibiting oxytocin-induced uterine contractions in vitro. Metabolite M1 is excreted in milk (see Use in pregnancy & lactation under Precautions).
There is no experience with atosiban treatment in patients with impaired function of the liver or kidneys (see Dosage & Administration and Precautions).
It is unlikely that the atosiban inhibits hepatic cytochrome P450 isoforms in humans (see Interactions).
Indications/Uses
Delay of imminent pre-term birth in pregnant women with: Regular uterine contractions of at least 30 sec duration at a rate of ≥4 per 30 min; cervical dilation of 1-3 cm (0-3 for nulliparas) and effacement of ≥50%; aged ≥18 years; gestational age from 24-33 completed weeks; 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.
Intravenous therapy using the initial bolus injection of Tractocile 7.5 mg/mL, solution for injection, should be started as soon as possible after diagnosis of pre-term labour. Once the bolus has been injected, proceed with the infusion.
Tractocile is administered IV in 3 successive stages: An initial bolus dose (6.75 mg), performed with Tractocile 7.5 mg/mL solution for injection, immediately followed by a continuous high dose infusion (loading infusion 300 mcg/min) of Tractocile 7.5 mg/mL concentrate for solution for infusion during 3 hrs, followed by a lower dose of Tractocile 7.5 mg/mL concentrate for solution for infusion (subsequent infusion 100 mcg/min) 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 330.75 mg of the active substance.
In the case of persistence of uterine contractions during treatment with Tractocile, alternative therapy should be considered.
There is no experience with atosiban 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 atosiban is excreted in the urine. In patients with impaired hepatic function, atosiban should be used with caution.
The following shows the full dosage of the bolus injection followed by the infusion:
Step 1: Regimen: 0.9 mL IV bolus. Injection/Infusion Rate: >1 min. Atosiban Dose: 6.75 mg
Step 2: Regimen: 3 hrs IV loading infusion. Injection/Infusion Rate: 24 mL/hr. Atosiban Dose: 18 mg/hr.
Step 3: Regimen: Up to 45 hrs subsequent IV infusion. Injection/Infusion Rate: 8 mL/hr. Atosiban Dose: 6 mg/hr.
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 for solution for infusion.
Overdosage
Few cases of atosiban overdosing were reported. They occurred without any specific signs or symptoms. There is no known specific treatment in case of an overdose.
Contraindications
Hypersensitivity to atosiban or any other ingredients of Tractocile. Gestational age <24 weeks or >33 weeks; premature rupture of the membranes >30 weeks of gestation; insufficient foetal growth and an abnormal foetal heart rate; uterine bleeding that requires immediate delivery; severe preeclampsia (high blood pressure, fluid retention and/or protein in the urine) or eclampsia (convulsions associated with preeclampsia) requiring delivery; death of foetus; suspected intrauterine infection; placenta praevia; abruptio placenta; conditions in which continuation of pregnancy is hazardous.
Special Precautions
When premature rupture of the membrane cannot be excluded, the benefits of delaying delivery should be balanced against the potential risk of chorioamnionitis.
There is no experience with atosiban treatment in patients with impaired function of the liver or kidneys (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Atosiban has not been used in patients with abnormal placental site.
There is only limited clinical experience in the use of atosiban in multiple pregnancies or pregnancy 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 (see Dosage & Administration).
Monitoring of uterine contractions and the foetal heart rate during administration of atosiban 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 clinical trials.
Multiple pregnancy and tocolytics like calcium channel blockers and β-mimetics are known to be associated with increased risk of pulmonary oedema. Therefore, atosiban should be used with caution in case of multiple gestations and/or concomitant administration of other tocolytics.
Effects on the Ability to Drive or Operate Machinery: Not applicable.
Use in pregnancy & lactation: Atosiban should only be used when pre-term labour has been diagnosed between 24 and 33 completed weeks of gestation.
If during pregnancy the woman is already breastfeeding an earlier child, then breastfeeding should be discontinued during treatment with Tractocile, since the release of oxytocin during breastfeeding may augment uterine contractility, and may counteract the effect of tocolytic therapy. In atosiban clinical trials, no effects were observed on breastfeeding. Small amounts of atosiban have been shown to pass from plasma into the breast milk of breastfeeding women.
Embryofoetal toxicity studies have not shown toxic effects of atosiban. No studies were performed that covered fertility and early embryonic development.
Use In Pregnancy & Lactation
Atosiban should only be used when pre-term labour has been diagnosed between 24 and 33 completed weeks of gestation.
If during pregnancy the woman is already breastfeeding an earlier child, then breastfeeding should be discontinued during treatment with Tractocile, since the release of oxytocin during breastfeeding may augment uterine contractility, and may counteract the effect of tocolytic therapy. In atosiban clinical trials, no effects were observed on breastfeeding. Small amounts of atosiban have been shown to pass from plasma into the breast milk of breastfeeding women.
Embryofoetal toxicity studies have not shown toxic effects of atosiban. No studies were performed that covered fertility and early embryonic development.
Adverse Reactions
Possible adverse reactions of atosiban were described for the mother during the use of atosiban in clinical trials. The observed adverse reactions were generally of mild severity. In total, 48% of the patients treated with atosiban-experienced adverse reactions.
For the newborn, the clinical trials did not reveal any specific adverse reactions of atosiban. The infant adverse events were in the range of normal variation and were comparable with both the placebo and β-mimetic group incidences.
The adverse reactions in the women were the following: Immune System Disorders: Rare (≥0.01-<0.1%): Allergic reaction.
Metabolism and Nutrition Disorders: Common (≥1-<10%): Hyperglycaemia.
Psychiatric Disorders: Uncommon (≥0.1-<1%): Insomnia.
Nervous System Disorders: Common (≥1-<10%): Headache, dizziness.
Cardiac Disorders: Common (≥1-<10%): Tachycardia.
Vascular Disorders: Common (≥1-<10%): Hypotension.
Gastrointestinal Disorders: Very Common (≥10%): Nausea. Common (≥1-<10%): Vomiting.
Skin and Subcutaneous Tissue Disorders: Uncommon (≥0.1-<1%): Pruritus, rash.
Reproductive System and Breast Disorders: Rare (≥0.01%-<0.1%): Uterine haemorrhage, uterine atony.
General Disorders and Administration Site Conditions: Common (≥1-<10%): Hot flushes, injection site reaction. Uncommon (≥0.1-<1%): Fever.
Respiratory events like dyspnoea and pulmonary oedema, particularly in association with concomitant administration of other tocolytics like calcium antagonists and β-mimetics and/or multiple pregnancy, have been reported during the post-marketing.
Drug Interactions
It is unlikely that atosiban is involved in cytochrome P450 mediated drug-drug interactions, as in vitro investigations have shown that atosiban is not a substrate for the cytochrome P450 system and does not inhibit the drug metabolising cytochrome P450 enzymes.
Interaction studies were performed in healthy, female volunteers with betamethasone and labetalol. No clinically relevant interaction was observed between atosiban and betamethasone. When atosiban 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 atosiban pharmacokinetics.
No interaction study has been performed with antibiotics, ergot alkaloids and antihypertensive agents other than labetalol.
Incompatibilities: In the absence of incompatibility studies, Tractocile should not be mixed with other medicinal products.
Caution For Usage
Instructions for Use and Handling: Solution for Injection: The vials should be inspected visually for particulate matter and discoloration prior to administration.
Preparation of Initial IV Injection: Withdraw 0.9 mL of 0.9 mL labelled vial of Tractocile 7.5 mg/mL, solution for injection and administer slowly as an IV bolus dose >1 min, under adequate medical supervision in an obstetric unit. The Tractocile 7.5 mg/mL, solution for injection should be used immediately.
In the absence of incompatibility studies, Tractocile must not be mixed with other medicinal products (see Incompatibilities).
Concentrate for Solution for Infusion: The vials should be inspected visually for particulate matter and discoloration prior to administration.
Preparation of the IV Infusion Solution: For IV infusion, the following bolus dose, Tractocile 7.5 mg/mL, concentrate for solution for infusion should be diluted in 1 of the following solutions: 0.9% w/v sodium chloride solution; 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 for solution for infusion from two (2) 5 mL vials to obtain a concentration of atosiban 75 mg in 100 mL. The loading infusion is given by infusing 24 mL/hr (ie, 18 mg/hr) of the above prepared solution >3 hrs 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.
In the absence of incompatibility studies, Tractocile must 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 the infusion.
Storage
Store in the original container at 2-8°C.
Shelf-Life: 4 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.
Presentation/Packing
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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