Atosiban Hybio

Clear, colorless solution without particles.
ATOSIBAN HYBIO 6.75 MG/0.9 ML SOLUTION FOR INJECTION: Each vial of 0.9 ml solution contains: Atosiban as acetate 6.75 mg.
ATOSIBAN HYBIO 37.5 MG/5 ML CONCENTRATE FOR SOLUTION FOR INFUSION: Each vial of 5 ml solution contains: Atosiban as acetate 37.5 mg.
Excipients/Inactive Ingredients: Mannitol, Hydrochloric acid, Water for injections.

Pharmacotherapeutic group: Other gynecologicals. ATC code: G02CX01.
Pharmacology: Pharmacodynamics: Mechanism of action: Atosiban HYBIO contains atosiban (INN), a synthetic peptide ([Mpa¹, D-Tyr (Et)², Thr⁴, Orn⁸]-oxytocin) which is a competitive antagonist of human oxytocin at the receptor level. In rats and guinea pigs, atosiban was shown to bind to oxytocin receptors and 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.
Pharmacodynamic 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 (≤4 contractions/hour) for 12 hours.
Clinical efficacy and safety: 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 hours 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.
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.
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).
Paediatric population: The safety and efficacy of atosiban in pregnant women aged less than 18 years have not been established. No data are available.
Pharmacokinetics: Absorption: 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).
Distribution: 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.
Biotransformation: 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.
Elimination: 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. The main metabolite M1 is approximately 10 times less potent than atosiban in inhibiting oxytocin-induced uterine contractions in vitro. Metabolite M1 is also excreted in milk.
Half-life: Following completion of the infusion, plasma concentration declined rapidly with an initial (tα) and terminal (tβ) half-life of 0.21±0.01 and 1.7±0.3 hours, respectively.
Clearance: Mean value for clearance was 41.8±8.2 litres/hour.
Patients with renal or liver impairment: 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.
Linearity/non-linearity: 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.

Atosiban 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%; age ≥18 years; a gestational age from 24 until 33 completed weeks; a normal fetal heart rate.

Recommended Dose: Treatment with Atosiban HYBIO should be initiated and maintained by a physician experienced in the treatment of pre-term labour.
Atosiban HYBIO is administered intravenously in three successive stages: An initial bolus dose (6.75 mg), performed with Atosiban HYBIO 6.75 mg/0.9 ml solution for injection, immediately followed by a continuous high dose infusion (loading infusion 300 micrograms/min) of Atosiban HYBIO 37.5 mg/5 ml concentrate for solution for infusion during three hours.
Followed by a lower dose of Atosiban HYBIO 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 Atosiban HYBIO therapy should preferably not exceed 330.75 mg of atosiban.
Intravenous therapy using the initial bolus injection (Atosiban HYBIO 6.75 mg/0.9 ml) should be started as soon as possible after diagnosis of pre-term labour. Once the bolus has been injected, proceed with the infusion (Atosiban HYBIO 37.5 mg/5 ml). In the case of persistence of uterine contractions during treatment with Atosiban HYBIO, alternative therapy should be considered.
The following table shows the full posology of the bolus injection followed by the infusion: See Table 1.

Click on icon to see table/diagram/image

Re-treatment: In case a re-treatment with atosiban is needed, it should also commence with a bolus injection of Atosiban HYBIO 6.75 mg/0.9 ml solution for injection followed by infusion with Atosiban HYBIO 37.5 mg/5 ml concentrate for solution for infusion.
Patients with renal or hepatic impairment: 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.
Paediatric population: The safety and efficacy of atosiban in pregnant women aged less than 18 years have not been established. No data are available.
Mode of Administration: The vials should be inspected visually for particulate matter and discoloration prior to administration.
Preparation of the initial intravenous injection (Atosiban HYBIO 6.75 mg/0.9 ml): Withdraw 0.9 ml of a 0.9 ml labelled vial of atosiban 6.75 mg/0.9 ml, solution for injection and administer slowly as an intravenous bolus dose over one minute, under adequate medical supervision in an obstetric unit. The atosiban 6.75 mg/0.9 ml, solution for injection should be used immediately.
Preparation of the intravenous infusion (Atosiban HYBIO 37.5 mg/5 ml): The intravenous infusion is prepared by diluting Atosiban HYBIO 37.5 mg/5 ml, concentrate for solution for infusion in sodium chloride 9 mg/ml (0.9%) solution for injection, Ringer's lactate solution or 5% w/v glucose solution. This is done by removing 10 ml of solution from a 100 ml infusion bag and replacing it with 10 ml Atosiban HYBIO 37.5 mg/5 ml concentrate for solution for infusion from two 5 ml vials to obtain a concentration of 75 ml atosiban in 100 ml. If an infusion bag with a different volume is used, a proportional calculation should be made for the preparation.
The reconstituted product is a clear, colourless solution without particles.
Atosiban HYBIO should not be mixed with other medicinal products in the infusion bag.
If other medicinal product needs 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.
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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.

Atosiban HYBIO must not be used in the following conditions: Hypersensitivity to the active substance(s) or to any of the excipients (Mannitol, Hydrochloric acid).
Gestational age below 24 or over 33 completed weeks.
Premature rupture of the membranes >30 weeks of gestation.
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.

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 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 atosiban 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 atosiban 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.
Multiple pregnancy and medicinal products with tocolytic activity like calcium channel blockers and betamimetics are known to be associated with increased risk of pulmonary oedema. Therefore, atosiban should be used with caution in case of multiple pregnancy and/or concomitant administration of other medicinal products with tocolytic activity.
Respiratory events like dyspnoea and pulmonary oedema, particularly in association with concomitant administration of other medicinal products with tocolytic activity, like calcium antagonists and betamimetics, and/or in women with multiple pregnancy, have been reported post-marketing.
Patients with renal or hepatic impairment: 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.

Pregnancy: Atosiban should only be used when pre-term labour has been diagnosed between 24 and 33 completed weeks of gestation.
Breast-feeding: If during pregnancy the woman is already breast-feeding an earlier child, then breast-feeding should be discontinued during treatment with atosiban, since the release of oxytocin during breast-feeding may augment uterine contractility, and may counteract the effect of tocolytic therapy. In atosiban clinical trials no effects were observed on breast-feeding. Small amounts of atosiban have been shown to pass from plasma into the breast milk of breast-feeding women.

Possible adverse reactions of atosiban were described for the mother during the use of atosiban in clinical trials. In total 48% of the patients treated with atosiban 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 new-born, the clinical trials did not reveal any specific adverse reactions of atosiban. The infant adverse reactions were in the range of normal variation and were comparable with both placebo and betamimetic group incidences.
The frequency of adverse reactions listed as follows 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. (See Table 2.)

Click on icon to see table/diagram/image

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 betamimetics, 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 Health Product Vigilance Center (HPVC) in Thailand.

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 have been performed with labetalol and betamethasone in healthy, female volunteers. No clinically relevant interaction was found between atosiban and bethamethasone or labetalol.

Store in a refrigerator (2°C - 8°C).
Store in the original package in order to protect from light.
Once the vial has been opened, the product must be used immediately.
Diluted solution for intravenous administration should be used within 24 hr. after preparation.

Drugs Acting on the Uterus

G02CX01 - atosiban ; Belongs to the class of other gynecologicals. Used to inhibit uncomplicated premature labour between 24 and 33 weeks of gestation.

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