1. Name Of The Medicinal Product
TRACTOCILE 7.5 mg/ml solution for injection
2. Qualitative And Quantitative Composition
One ml solution contains 7.5 mg atosiban free-base in the form of atosiban acetate.
For excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection
Visual appearance: clear, colourless solution without particles.
4. Clinical Particulars
4.1 Therapeutic Indications
TRACTOCILE is indicated to delay imminent pre-term birth in pregnant women with:
− regular uterine contractions of at least 30 seconds duration at a rate of
− a cervical dilation of 1 to 3 cm (0-3 for nulliparas) and effacement of
− age
− a gestational age from 24 until 33 completed weeks
− a normal fetal heart rate
4.2 Posology And Method Of Administration
Treatment with TRACTOCILE should be initiated and maintained by a physician experienced in the treatment of pre-term labour.
TRACTOCILE is administered intravenously in three 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 micrograms/min) of TRACTOCILE 7.5 mg/ml concentrate for solution for infusion during three hours, followed by a lower dose of TRACTOCILE 7.5 mg/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 TRACTOCILE therapy should preferably not exceed 330 mg of the active substance.
Intravenous 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 (See Summary of Product Characteristics of TRACTOCILE 7.5 mg/ml, concentrate for solution for 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:
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Re-treatment
In case a re-treatment with atosiban 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.
4.3 Contraindications
TRACTOCILE should 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
− Intrauterine growth retardation and abnormal fetal heart rate
− Antepartum uterine haemorrhage requiring immediate delivery
− Eclampsia and severe pre-eclampsia requiring delivery
− Intrauterine fetal death
− Suspected intrauterine infection
− Placenta praevia
− Abruptio placenta
− Any other conditions of the mother or fetus, in which continuation of pregnancy is hazardous
− Known hypersensitivity to the active substance or any of the excipients.
4.4 Special Warnings And Precautions For Use
When atosiban 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 atosiban treatment in patients with impaired function of the liver or kidneys (see sections 4.2 and 5.2).
Atosiban has not been used in patients with an abnormal placental site.
There is only limited clinical experience in the use of atosiban in multiple pregnancies or the gestational age group between 24 and 27 weeks, because of the small number of patients treated. The benefit of atosiban 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 section 4.2).
In case of intrauterine growth retardation, the decision to continue or reinitiate the administration of TRACTOCILE depends on the assessment of fetal maturity.
Monitoring of uterine contractions and fetal 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 the clinical trials.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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-administrated, Cmax of labetalol was decreased by 36% and Tmax increased by 45 minutes. 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 anti-hypertensive agents other than labetalol.
4.6 Pregnancy And Lactation
Atosiban should only be used when pre-term labour has been diagnosed between 24 and 33 completed weeks of gestation.
In atosiban 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.
Embryo-fetal toxicity studies have not shown toxic effects of atosiban. No studies were performed that covered fertility and early embryonic development (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
Possible undesirable effects of atosiban were described for the mother during the use of atosiban in clinical trials. The observed undesirable effects were generally of a mild severity. In total 48% of the patients treated with atosiban 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 beta-mimetic group incidences.
The undesirable effects in the women were the following:
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4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other gynecologicals, ATC code: G02CX01
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 uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence (
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 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 tocolytics within 7 days of treatment initiation was similar for atosiban 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 atosiban 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 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) grams in the atosiban group and 2461 (831) grams 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 one re-treatment, 8 received at least 2 re-treatments and 2 received 3 re-treatments (see section 4.4).
As the safety and efficacy of atosiban 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 atosiban is not recommended (see section 4.3).
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 two occurred at five and eight months of age. Eleven out of the 15 deaths in the atosiban group occurred in pregnancies with a gestational age of 20 to 24 weeks, although in this subgroup patient distribution was unequal (19 women on atosiban, 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 atosiban group).
5.2 Pharmacokinetic Properties
In healthy non-pregnant subjects receiving atosiban 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.
In women in pre-term labour receiving atosiban 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. Mean value of volume of distribution was 18.3 ± 6.8 litres.
Plasma protein binding of atosiban is 46 to 48% in pregnant women. It is not known whether the free fraction in the maternal and fetal compartments differs substantially. Atosiban does not partition into red blood cells.
Atosiban passes the placenta. Following an infusion of 300 micrograms/min in healthy pregnant women at term, the fetal/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 second hour 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 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 (see section 4.6).
There is no experience with atosiban treatment in patients with impaired function of the liver or kidneys (see sections 4.2 and 4.4).
It is unlikely that atosiban inhibits hepatic cytochrome P450 isoforms in humans (see section 4.5).
5.3 Preclinical Safety Data
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 atosiban 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.
Atosiban was neither oncogenic nor mutagenic in in vitro and in vivo tests.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Mannitol
Hydrochloric acid 1M
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
2 years.
Once the vial has been opened, the product must be used immediately.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C - 8°C).
Store in the original package.
6.5 Nature And Contents Of Container
One vial of solution for injection contains 0.9 ml solution, corresponding to 6.75 mg atosiban.
Colourless glass vials, clear borosilicated (type I) sealed with grey siliconised bromo-butyl rubber stopper, type I, and flip-off cap of polypropylene and aluminium.
6.6 Special Precautions For Disposal And Other Handling
The vials should be inspected visually for particulate matter and discoloration prior to administration.
Preparation of the initial intravenous injection:
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 intravenous bolus dose over one minute, 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 compatibility studies, this medicinal product must not be mixed with other medicinal products (see section 6.2).
7. Marketing Authorisation Holder
Ferring AB
Soldattorpsvägen 5
Box 30 047
SE - 20061 - Limhamn
Sweden.
8. Marketing Authorisation Number(S)
EU/1/99/124/001.
9. Date Of First Authorisation/Renewal Of The Authorisation
20 January 2005.
10. Date Of Revision Of The Text
January 2005.
11. LEGAL CATEGORY
POM.
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