Tosiban

Uses

Tosiban is used 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 fetal heart rate

Tosiban is also used to associated treatment for these conditions: Delaying imminent pre-term birth

How Tosiban works

Tosiban is a synthetic peptide oxytocin antagonist . It resembles oxytocin with has modifications at the 1, 2, 4, and 8 positions. The N-terminus of the cysteine residue is deaminated to form 3-mercaptopropanic acid at position 1, at position 2 L-tyrosine is modified to D-tyrosine with an ethoxy group replacing the phenol , threonine replaces glutamine at postion 4, and ornithine replaces leucine at position 8.

It binds to membrane bound oxytocin receptors on the myometrium and prevents oxytocin-stimulated increases in inositol triphosphate production . This ultimately prevents release of stored calcium from the sarcoplasmic reticulum and subsequent opening of voltage gated calcium channels. This shutdown of cytosolic calcium increase prevents contractions of the uterine muscle, reducing the frequency of contractions and inducing uterine quiescence.

Tosiban has more recently been found to act as a biased ligand at oxytocin receptors . It acts as an antagonist of Gq coupling, explaining the inhibition of the inositol triphosphate pathway thought to be responsible for the effect on uterine contraction, but acts as an agonist of Gi coupling. This agonism produces a pro-inflammatory effect in the human amnion, activating pro-inflammatory signal tranducer NF-κB . It is thought that this reduces atosiban's effectiveness compared to agents which do not produce inflammation as inflammatory mediators are known to play a role in the induction of labour.

Dosage

Tosiban dosage

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 atosiban.

Side Effects

Very common (affects more than 1 in 10 people): feeling sick (nausea).

Common (affects less than 1 in 10 people): headache, feeling dizzy, hot flushes, being sick (vomiting), fast heartbeat, Low blood pressure. Signs may include feeling dizzy or light-headed, A reaction at the site where the injection was given, high blood sugar.

Uncommon (affects less than 1 in 100 people): high temperature (fever), difficulty sleeping (insomnia), itching, rash.

Toxicity

No systemic toxicities were found in rat and dog studies at dosages equivalent to 10 times normal human exposure . It is thought that the risk of toxicity is low due to the short duration of action and short half life of atosiban .

Precaution

• 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.
• 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 beta- mimetics 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

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

Food Interaction

Volume of Distribution

Tosiban has a mean volume of distribution of 41.8 L. Tosiban crosses the placenta and, at a dose of 300 μg/min, was found to have a 0.12 maternal/fetal concentration ratio .

Elimination Route

In women receiving 300 μg/min by infusion for 6-12 h, average steady state concentrations of 442 ng/mL were reached within 1 h . Steady state concentrations increase proportionally to dosage.

Half Life

Tosiban does not conform to either 1-compartment or 2-compartment kinetics. It has been determined to have an initial half life (tα) of 0.21 h and a terminal half life (tβ) of 1.7 h .

Clearance

Tosiban has a mean clearance rate of 41.8 L/h .

Elimination Route

Small amounts of atosiban are found in the urine with 50 times the amount appearing as the large fragment metabolite (des-(Orn⁸, Gly⁹-NH2)-[Mpa¹, D-Tyr(Et)², Thr⁴]-oxytocin . The amount of drug excreted in the feces is not known.

Pregnancy & Breastfeeding use

If you are pregnant and breast-feeding an earlier child, you should stop breast-feeding while you are given
Tosiban.

Contraindication

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

Storage Condition

Store in a refrigerator (2°C-8°C). Keep away from light & moisture. Keep out of the reach of children.

Innovators Monograph

You find simplified version here Tosiban