Tosiban 6.75mg Injection

Atosiban Acetate Solution for Injection (7.5mg/ml)

Atosiban Acetate Concentrate for Solution for Infusion (7.5mg/ml)

Tosiban 6.75 mg Solution for Injection

Each 0.9 ml contains:

Atosiban Acetate IP equivalent to Atosiban 6.75 mg

Water for Injections IP q.s.

Tosiban® 37.5 mg concentrate for solution for infusion

Each 5 ml contains:

Atosiban acetate IP equivalent to Atosiban  37.5 mg

Water for injection IP q.s

Solution for injection and Infusion (For IV Use only).

7.5 mg/ml

4.1. Therapeutic indication

Tosiban^® 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

4.2. Posology and method of administration

Posology

Treatment with Tosiban^® should be initiated and maintained by a physician experienced in the treatment of pre-term labour.

Tosiban^® is administered intravenously in three successive stages: an initial bolus dose (6.75 mg), performed with Tosiban^® 6.75 mg/0.9 ml solution for injection, immediately followed by a continuous high dose infusion (loading infusion 300 micrograms/min) of Tosiban^® 37.5 mg/5 ml concentrate for solution for infusion during three hours, followed by a lower dose of Tosiban^® 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 Tosiban® therapy should preferably not exceed 330.75 mg of Tosiban^®.

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. In the case of persistence of uterine contractions during treatment with Tosiban^®, alternative therapy should be considered. The following table shows the full posology of the bolus injection followed by the infusion:

Methods of administration

Step 1: Preparation of the initial intravenous injection (Bolus):

Give a bolus dose directly intravenously using 1ml syringe. Withdraw 0.9 ml of Tosiban 6.75 mg Solution for Injection and administer slowly as an intravenous bolus dose over one minute, under adequate medical supervision in an obstetric unit.

Step 2 and 3 Method of administration:

Preparation of the intravenous infusion solution: For intravenous infusion, Tosiban injection 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.

A. Using 500 ml infusion bottles:

Preparation of the intravenous infusion solution when given in 500 ml Infusion Bottle: Withdraw 7.5 ml solution from a 500 ml infusion bottle & discard. Replace it with 7.5 ml Tosiban solution for infusion (1.5 x 5 ml vials). Remaining half vial of Tosiban (2.5 ml) to be stored at 2°C to 8°C and used for preparation of subsequent infusion.

B. Using 100ml infusion bottles

Preparation of the intravenous infusion solution when given in 100 ml Infusion Bottle/Bottle: Withdraw 7.5 ml solution from a 100 ml infusion bottle and discard. Replace it by 7.5 ml of Atosiban 37.5 mg/5 ml concentrate for solution for infusion.

Remaining half vial of Tosiban (2.5 ml) to be stored at 2°C to 8°C & used for preparation of subsequent infusion.

Re-treatment:

In case a re-treatment with Tosiban^® is needed, it should also commence with a bolus injection of Tosiban^® 6.75 mg/0.9 ml, solution for injection followed by infusion with Tosiban^® 37.5 mg/5 ml, concentrate for solution for infusion.

Patients with renal or hepatic impairment

There is no experience with Tosiban^® 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 Tosiban^® is excreted in the urine. In patients with impaired hepatic function, Tosiban^® should be used with caution.

Paediatric population

The safety and efficacy of Tosiban^® in pregnant women aged less than 18 years have not been established. No data are available.

4.3. Contraindications

Tosiban^® 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
• Hypersensitivity to the active substance(s) or to any of the excipients

4.4. Special warnings and precautions for use

When Tosiban® 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 Tosiban® 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 Tosiban® is excreted in the urine. In patients with impaired hepatic function, Tosiban® should be used with caution.

There is only limited clinical experience in the use of Tosiban® in multiple pregnancies or the gestational age group between 24 and 27 weeks, because of the small number of patients treated. The benefit of Tosiban® in these subgroups is therefore uncertain.

Re-treatment with Tosiban® 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 Tosiban® depends on the assessment of fetal maturity.

Monitoring of uterine contractions and fetal heart rate during administration of Tosiban® and in case of persistent uterine contractions should be considered.

As an antagonist of oxytocin, Tosiban® 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, Tosiban® should be used with caution in case of multiple pregnancy and/or concomitant administration of other medicinal products with tocolytic activity.

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

4.6. Fertility, pregnancy and lactation

Fertility

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).

Pregnancy

Tosiban^® 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 breast-feeding an earlier child, then breast-feeding should be discontinued during treatment with Tosiban®, since the release of oxytocin during breast-feeding may augment uterine contractility, and may counteract the effect of tocolytic therapy.

Breastfeeding

In Tosiban® clinical trials, no effects were observed on breast-feeding. Small amounts of Tosiban® have been shown to pass from plasma into the breast milk of breast-feeding women.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Possible adverse reactions of Tosiban^® were described for the mother during the use of Tosiban^® in clinical trials. In total 48% of the patients treated with Tosiban^® 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 Tosiban®. 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.

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 email to: medico@zuventus.com Website link: https://www.zuventus.co.in/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9. Overdose

Few cases of Tosiban® overdosing were reported, they occurred without any specific signs or symptoms. There is no known specific treatment in case of an overdose.

5.1 Pharmacodynamic properties

Mechanism of action

Tosiban^® 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.

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.

5.2 Pharmacokinetic properties

Absorption

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.

Distribution

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. Tosiban® 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 Tosiban® 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. 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 excreted in milk (see section 4.6).

Elimination

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 (see sections 4.2 and 4.4).

It is unlikely that atosiban inhibits hepatic cytochrome P450 isoforms in humans (see section 4.5).

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.

Tosiban^® contains atosiban acetate. It is a competitive antagonist of human oxytocin receptors and thus, decreases uterine contractions. Each ml of Tosiban^® solution contains 7.5 mg atosiban for solution for injection or infusion.

Chemical structure of atosiban.

Molecular Formula: C₄₃H₆₇N₁₁O₁₂S₂

Molecular Weight: 994.2 g/mol

8.1 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except mentioned in this section. For intravenous infusion, following the bolus dose, Tosiban^® 37.5 mg/5 ml, concentrate for solution for infusion should be diluted in one of the following solutions: - Sodium Chloride (0.9%) solution - Ringer's lactate solution - 5% w/v glucose solution.

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

Tosiban 6.75 mg: A vial of 0.9 ml.

Tosiban 37.5 mg: A vial of 5 ml.

8.4 Storage and handing instructions

Store at 2°C to 8°C. Do not freeze.

Store in the original package in order to protected from light.

Once the vial has been opened, the dilution must be performed immediately. Diluted solution for intravenous administration should be used within 24 hours’ after preparation.

The vial should be inspected visually for particulate matter & discoloration prior to administration.

Keep out of reach of children.

Talk to your doctor or nurse before you are given Tosiban^®:

• if you think your waters might have broken (premature rupture of your membranes).
• if you have kidney or liver problems.
• if you are pregnant with more than one baby.
• if your contractions start again, treatment with Tosiban^® can be repeated up to three more times.
• if your unborn baby is small for the time of your pregnancy.
• Your womb may be less able to contract after your baby has been born. This may cause bleeding.
• if you are pregnant with more than one baby and/or are given medicines that can delay the birth of your baby, such as medicines used for high blood pressure. This may increase the risk of lung oedema (accumulation of fluid in the lungs).

If any of the above apply to you (or you are not sure), talk to your doctor, before you are given Tosiban^®.

27th June 2024