1 Name of Medicine
Misoprostol.
2 Qualitative and Quantitative Composition
Each tablet contains 25 microgram misoprostol.
For the full list of excipients, see Section 6.1.
3 Pharmaceutical Form
Tablet.
White, uncoated oval shaped tablets with the dimensions 7.5 x 4.5 mm with a score line on one side and plain on the other. The score line is not intended for breaking the tablet.
4.1 Therapeutic Indications
Angusta is indicated for induction of labour.
4.2 Dose and Method of Administration
Dosage.
The recommended dosing regimen for Angusta is 25 microgram orally every two hours or 50 microgram orally every four hours according to hospital practice. The maximum dose is 200 microgram over a period of 24 hours.
There may be a synergistic/additive effect of misoprostol and oxytocin. Plasma concentrations of misoprostol acid are negligible after 5 half-lives (3.75 hours), see Section 5.2 Pharmacokinetic Properties. It is recommended to wait 4 hours after the last dose of Angusta before administration of oxytocin (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Method of administration.
Angusta should only be administered by trained obstetric personnel in a hospital setting where facilities for continuous foetal and uterine monitoring is available and the cervix should be assessed carefully before product use.
Angusta should be taken orally with a glass of water.
Dosage adjustment in patients with hepatic or renal impairment.
A lower dose and/or prolonged dosing intervals should be considered in pregnant women with renal or hepatic impairment (see Section 5.2 Pharmacokinetic Properties).
Paediatric population.
The safety and efficacy of Angusta in pregnant women aged less than 18 years has not been established in clinical trials. No data are available.4.3 Contraindications
Angusta is contraindicated:
When there is hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.
When labour has started.
When there is suspicion or evidence of foetal compromise prior to induction (e.g. failed non-stress or stress test, meconium staining or diagnosis or history of non-reassuring foetal status).
When oxytocic drugs and/or other labour induction agents are being given (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When there is suspicion or evidence of uterine scar resulting from previous uterine or cervical surgery, e.g. caesarean delivery.
When there is uterine abnormality (e.g. bicornuate uterus) preventing vaginal delivery.
When there is placenta praevia or unexplained vaginal bleeding after 24 weeks gestation with this pregnancy.
When there is foetal malpresentation, contraindicating vaginal delivery.
In patients with kidney failure (GFR < 15 mL/min/1.73 m2).
4.4 Special Warnings and Precautions for Use
Angusta should only be administered by trained obstetric personnel in a hospital setting where facilities for continuous foetal and uterine monitoring is available and the cervix should be assessed carefully before product use.
As there are limited clinical data with misoprostol in pregnant women with bishop score (mBS) > 6, Angusta is only recommended for use in patients with unfavourable cervix i.e. mBS ≤ 6.
Angusta can cause excessive uterine stimulation.
If uterine contractions are prolonged or excessive, or there is a clinical concern for the mother or baby, additional Angusta tablets should not be administered. If excessive uterine contractions continue, treatment according to local guidelines should be started.
In women with pre-eclampsia, evidence or suspicion of foetal compromise should be ruled out (see Section 4.3 Contraindications). There are no or limited clinical data with misoprostol in pregnant women with severe pre-eclampsia marked by haemolytic anaemia; elevated liver enzymes; low platelet count (HELLP) syndrome, other end organ affliction or CNS findings other than mild headache.
Chorioamnionitis may necessitate fast delivery. Decisions regarding antibiotic treatment, induced labour or caesarean section will be at the physician's discretion.
There are no or limited clinical data with misoprostol in women whose membranes have been ruptured for more than 48 hours prior to administration of misoprostol.
There may be synergistic/additive effects of misoprostol and oxytocin. Concomitant administration of oxytocin is contraindicated. See Section 4.3. Angusta is eliminated after 4 hours. See Section 5.2. It is recommended to wait 4 hours after last dose of Angusta before administration of oxytocin (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There are no or limited clinical data with misoprostol in multiple pregnancies. There are no or limited clinical data with misoprostol in grand multiparity.
There are no or limited clinical data with misoprostol before week 37 of gestation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Angusta should be used only when induction of labour is clinically indicated.
An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labour has been induced by any physiological or pharmacological method.
Use in hepatic and renal impairment.
A lower dose and/or prolonged dosing intervals should be considered in pregnant women with renal or hepatic impairment (see Section 5.2 Pharmacokinetic Properties).
Use in the elderly.
No data available.
Paediatric use.
The safety and efficacy of Angusta in pregnant women aged less than 18 years has not been established in clinical trials.
Effects on laboratory tests.
No data available. For investigations, please see Section 4.8 Adverse Effects (Undesirable Effects).4.5 Interactions with Other Medicines and Other Forms of Interactions
No interaction studies have been performed with Angusta.
Concurrent use of oxytocic drugs or other labour induction agents is contraindicated due to the potential of increased uterotonic effects (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
Studies of fertility and embryo development in rats have shown that misoprostol may have an impact on implantation and resorption. This is, however, considered of no relevance for the indicated use of Angusta in late pregnancy.
(Category X)
The definition of pregnancy Category X is drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.
Angusta has been studied in pregnant women ≥ 37 weeks of gestation.
Angusta should only be used prior to 37 weeks of gestation if medically indicated (see Section 4.4 Special Warnings and Precautions for Use).
Angusta is used for labour induction at a low misoprostol dosage for a short period of time at the very end of pregnancy. When used at that time of pregnancy, there is no risk of foetal malformations. Angusta should not be used at any other time during pregnancy: a threefold increased risk of foetal malformations (including Moebius syndrome, amniotic band syndrome and central nervous system anomalies) has been reported in pregnancies exposed to misoprostol in first trimester.
No studies have been performed to investigate the amount of misoprostol acid in colostrum or breast milk following the use of Angusta.
Misoprostol has been detected in human milk following oral administration of misoprostol in tablet form.
Pharmacokinetic trials reveal that oral misoprostol (at dose levels of 600 microgram and 200 microgram) is excreted into breast milk with drug levels that rise and fall very quickly. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 picogram/mL (% CV 37%) and 20.9 picogram/mL (% CV 62%) after single 200 microgram and 600 microgram misoprostol administration, respectively. Negligible amounts of misoprostol acid remain in maternal plasma after 5 half-lives (3.75 hours), and even lower concentrations will remain in breast milk.
As the amount of misoprostol in breast milk does not represent a significant exposure to the neonate, breast-feeding can start immediately after birth.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
The undesirable effects listed in Table 1 have been reported in 41 trials where a total of 3,152 women were exposed to oral misoprostol at doses of 20-25 microgram every 2 hours or 50 microgram every 4 hours. In addition, adverse events reported in a compassionate use program, where approximately 29,000 women have been exposed to Angusta for induction of labour are also listed.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at https://www.tga.gov.au/reporting-problems.4.9 Overdose
There is no information on overdose with Angusta.
In case of overdose symptoms (e.g. excessive uterine stimulation causing prolonged or excessive contractions), dosing with Angusta should be arrested and tocolytic agents such as betamimetics should be considered according to local guidelines. The potential consequences of uterine hyperstimulation include foetal heart rate disorders and asphyxia in which case caesarean section should be considered.
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Misoprostol is a synthetic analogue of prostaglandin E1 (PGE1), a naturally occurring oxytocic compound. Prostaglandins of the F and E series have been shown to increase collagenase activity in rabbit uterine cervix fibroblasts in vitro and to cause cervical ripening and uterine contraction in vivo. These pharmacodynamic effects are considered to be the mechanism of action relevant for the clinical effect of Angusta.
PGE analogues also have a number of other effects, e.g. relaxation of bronchial and tracheal muscles, increase of mucus secretion and decrease of acid and pepsin secretion in the stomach, increase of renal blood flow, increase of circulating concentrations of adrenocorticotropic hormone and prolactin. These pharmacodynamic effects are considered to be of no clinical importance with the short treatment.
Clinical trials.
Dosage 25 microgram 2-hourly.
Knowledge about efficacy and safety is based on meta-analyses of 4 clinical studies where 637 women were exposed to the dosing regimen, oral misoprostol 20-25 microgram 2-hourly. See Table 2.
In three of the trials (596 women), the main inclusion criterion was term pregnancy. For one trial (41 women), the main inclusion criterion was term pregnancy and prelabour rupture of membranes (PROM). The double-blind trial, Dodd 2006 is considered pivotal and is described in detail in the following.
Dodd 2006 was a randomised double-blind, double-dummy, active-controlled (vaginal dinoprostone gel) study (N=365/376). Women at term pregnancy (> 36 weeks + 6 days) with singleton pregnancies in cephalic presentation without complications and Bishop score < 7 were eligible. The primary endpoints were vaginal delivery not achieved within 24 hours, uterine hyperstimulation with foetal heart rate change (FHR) and caesarean sections.
There was no statistically significant difference between oral misoprostol and vaginal dinoprostone with regards to vaginal delivery not achieved within 24 hours (oral misoprostol 168/365 (46.0%) vs dinoprostone 155/376 (41.2%); relative risk 1.12, 95% confidence interval 0.95 to 1.32; P = 0.134). Non-inferiority was not established.
There was a lower (not statistically significant) risk in the oral misoprostol group for uterine hyperstimulation with foetal heart rate changes, caesarean section and low Apgar score. There was a statistically significant lower risk of uterine hyperstimulation without foetal heart rate changes in women treated with oral misoprostol. Patients in the misoprostol group had a statistically significant chance of requiring further intervention (either dinoprostone or oxytocin) than the dinoprostone group. There was no difference in the secondary outcomes such as neonatal cord pH and blood loss.
Dosage 50 microgram 4-hourly.
Knowledge about efficacy and safety is based on meta-analyses of 23 clinical trials where 2,515 women were exposed to the dosing regimen, oral misoprostol 50 microgram 4-hourly. See Table 3.
The main inclusion criterion in all three placebo controlled trials was PROM.
In one study comparing against oxytocin, the main inclusion criterion was PROM (55 women) and in the other study the main inclusion criterion was term pregnancy (36 women).
All three studies comparing against dinoprostone (administered vaginally or intracervically) were open label studies. In one study, the main inclusion criterion was PROM (31 patients) whereas the main inclusion criterion was term pregnancy (124 women) for the other two studies.
Three of the studies comparing against vaginal misoprostol were double blind studies (215 women were exposed). In one double-blind study, the main inclusion criterion was PROM (51 women). In the two other double-blind studies, the main inclusion criterion was term pregnancy (164 women). The remaining seven studies were open label studies with the main inclusion criterion being term pregnancy (652 women).
An additional 5 studies (1155 women) compared to various comparators such as titrated misoprostol, higher dose misoprostol, combinations of oxytocin and PGE gel; and Foley catheter. These trials are supportive for safety, only.
The double-blind trials Bennett 1998 and Levy 2007 are considered pivotal and are described in detail in the following.
Bennett 1998 was a randomised double-blind active controlled (vaginal misoprostol) study (N=104/102) comparing oral to vaginal use of 50 microgram of misoprostol administered every 4 hours in women at term with intact membranes. The study stratified for low (< 7) or high (≥ 7) Bishop score. The primary endpoint was time from induction to vaginal birth. Other endpoints were frequency of excessive uterine activity resulting in abnormal foetal heart rate (FHR), neonatal morbidity (as measured by cord blood acid-base analysis and ACOG criteria for birth asphyxia), caesarean birth, maternal gastrointestinal side effects, and patient satisfaction.
Time from induction to delivery was statistically significantly shorter with vaginal misoprostol than with oral misoprostol (14.1 hours vs 17.9 hours, p=0.004).
For other outcomes, such as risk of uterine hyperstimulation with foetal heart rate changes and caesarean section, there was a lower (not statistically significant) risk in the oral misoprostol group. There was a statistically significantly lower risk of uterine hyperstimulation without foetal heart rate changes in the oral misoprostol group.
Levy 2007 was a double-blind study (N=64/66) investigating the 50 microgram 4-hourly posology against placebo in women with prelabour rupture of membranes (PROM). The primary endpoint was delivery within 24 hours from PROM.
The time to delivery was statistically significantly shortened with oral misoprostol compared to placebo with only a slight (not statistically significant) increase in the frequency of uterine hyperstimulation. For other safety outcomes, such as risk of caesarean section, there appeared to be a lower risk in the oral misoprostol group (not statistically significant). No neonates had an Apgar score less than 7 at 5 min.
The clinical study (AZ-201) supports the safety and efficacy of Angusta for induction of labour.
5.2 Pharmacokinetic Properties
Misoprostol, an ester, is rapidly metabolised to its active metabolite misoprostol acid. Only misoprostol acid is detectable in plasma. The acid is further metabolised by beta fatty acid oxidation to inactive dinor and tetranor acid metabolites prior to excretion in the urine.
Absorption.
After oral administration of Angusta, misoprostol is rapidly absorbed, with peak plasma levels of the active metabolite (misoprostol acid) occurring after approximately 30 minutes.
The dose normalised AUC following 25 and 50 microgram misoprostol (Angusta) were not statistically significantly different. Mean±SD were 107.8±53.16 and 128.1±45.60 h.picogram/mL, respectively.
Distribution.
The serum protein binding of misoprostol acid is less than 90% and concentration independent at therapeutic doses.
Metabolism.
Administration of misoprostol with food does not change the bioavailability of misoprostol acid, but reduces the maximum plasma concentration due to a slower absorption rate.
Excretion.
The mean plasma elimination half-life of misoprostol acid is approximately 45 minutes.
Renal or hepatic impairment.
There are studies showing a trend towards higher Cmax, AUC and t½ in patients with renal or hepatic impairment.
5.3 Preclinical Safety Data
Genotoxicity.
Misoprostol was negative in a battery of 5 in vitro assays and one in vivo test to assess mutagenic potential.
Carcinogenicity.
In carcinogenicity studies in the rat and mouse it was concluded that there was no risk of carcinogenic hazard.6 Pharmaceutical Particulars
6.1 List of Excipients
Hypromellose, microcrystalline cellulose, maize starch, crospovidone, croscarmellose sodium, colloidal anhydrous silica.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C. Store in the original package in order to protect from moisture.
6.5 Nature and Contents of Container
Angusta is available in a pack of double layer aluminium foil blister containing 8 tablets.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Misoprostol is a water soluble, viscous liquid. Misoprostol is a synthetic prostaglandin E1 analogue. Misoprostol has a molecular formula of C22H38O5 and a molecular weight of 382.5.
Chemical structure.
The molecular structure of misoprostol is:
CAS number.
59122-46-2.7 Medicine Schedule (Poisons Standard)
(S4) Prescription only medicine.
