drug product information ( pi ) provides details on the approved clinical use of drugs listed by the therapeutic goods administration ( tga ) in australia .
information included in pis is derived from clinical trials that support the use of a drug in each of these areas .
based on the pharmacology of a drug in relation to its approved indication , however , treatment of other medical conditions not listed on the pi may also be rationalised .
off - label prescribing occurs when a drug is prescribed for one or more criteria that are not included in the pi and , as such , information regarding appropriate dose for the condition or population group , pharmacokinetics / pharmacodynamics , and potential adverse effects may not be available in the pi or consumer medicines information ( cmi ) .
nevertheless , off - label prescribing may be justified by good quality evidence from clinical trials or systematic reviews of the literature , and a number of examples have been accepted in general and specialist clinical practice .
for example , until recently misoprostol was only approved by the tga for treatment and prevention of upper gastrointestinal ( gi ) ulceration .
it is commonly used off - label in obstetrics for treatment of post - partum haemorrhage as part of a management algorithm since it has demonstrated effective haemorrhage prevention and control in combination with oxytocin ( tuncalp et al . , 2012 ) .
regimes for use of misoprostol in gynaecology to evacuate the contents of a gravid uterus , in both miscarriage and abortion have also been described ( gomez ponce de leon et al . , 2007 ) and evaluated ( dodd and crowther , 2010 ) .
recently , misoprostol has also been approved in australia for use in combination with mifepristone to terminate pregnancy in women of child - bearing age .
misoprostol ( 15-deoxy-16-hydroxy-16-methyl pge1 ) is an orally active synthetic prostaglandin e1 ( pge1 ) methyl ester analogue . after oral administration , misoprostol rapidly de - esterifies to its biologically active form , misoprostolic acid .
it has four major effects : gastrointestinalcytoprotection ( approved therapeutic indication ) , uterotonicity , and diarrhoea and abdominal pain which are regarded as adverse effects .
cytoprotective effect is mainly by topical contact , with inhibition of gastric acid secretion and induction of oedema of the mucosa and submucosa , increasing the thickness of both layers .
uterotonicity requires binding to receptors in uterine smooth muscle and are mediated systemically after oral dosing .
abdominal pain , diarrhoea and flatulence are probably the result of exposure to the released misoprostolic acid and correlate well with the timing and magnitude of the misoprostolic acid peak plasma concentration ( davies et al . , 2001 ) .
mifepristone ( also known as ru-486 ) is a synthetic antiprogestin steroid with high affinity for the glucocorticoid and progesterone receptors and a weak affinity for the androgen receptor .
mifepristone acts by binding to the human uterine progesterone receptor with twice the affinity of that of progesterone , thus competitively inhibiting the endometrial and myometrial effects effect of progesterone . under some circumstances , in the absence of progesterone , mifepristone may also act as a progesterone agonist ( robbins and spitz , 1996 ) .
its mechanism of action at the cellular level is highly complex and a variety of hypotheses have been proposed . during
pregnancy mifepristone sensitises the myometrium to the contraction inducing action of prostaglandins ( swahn and bygeeman , 1988 ) .
administration of mifepristone in early pregnancy results in regular uterine contractility and increased sensitivity to prostaglandins . moreover , with high concentrations of progesterone , blockage of decidual progesterone receptors by mifepristone results in withdrawal of progesterone support to the endometrium , leading to uterine bleeding and disruption of placental function .
first trimester actions also include reduced cervical resistance , dilatation and opening of the cervix .
mifepristone was first registered for medical abortion in europe in 1988 and now has registration in many countries worldwide
. from 1996 to 2005 in australia mifepristone was classified as a  restricted good  which could only be imported with written approval of the federal minister for health . in 2006 the therapeutic goods amendment ( repeal of ministerial responsibility for approval of ru486 ) bill 2005
was passed in parliament which enabled the tga to assess the efficacy , safety and quality of mifepristone should any application for registration be made .
no drug sponsor made immediate application for registration to the tga so mifepristone remained an unapproved drug in australia .
it was , however , available to authorised prescribers under provisions of the therapeutic goods act 1989 which permitted importation and use of drugs recognised and used overseas but that were currently unavailable in australia . in 2012 , mifepristone ( therapeutic goods administration , 2014 ) was approved for use in 
 combination with misoprostol ( therapeutic goods administration , 2012 ) for medical abortion in women of child - bearing age .
prescription is restricted to clinicians who have undertaken defined women s health training administered by the drug sponsor , and who have registered on the specific prescribing program .
medical termination of a developing intra- uterine pregnancy up to 63 days of gestation , in sequential combination with a prostaglandin analogue ; and 2 .
preparation for the action of registered prostaglandin analogues that are indicated for the termination of pregnancy for medical reasons beyond the first trimester .
combined mifepristone and misoprostol has reported widespread use for early first trimester abortions and has been the subject of a number of reviews ( kulier et al . , 2011 ; raymond et al . , 2013 )
the combination has an acceptable safety profile in clinical practice ( goldstone et al . , 2012 ;
cleland et al.,2013 ) and controlled administration for abortion in outpatient and home settings has also been successfully performed even prior to formal registration of these drugs in australia ( de costa et al .
. nevertheless , significant adverse events including incomplete abortion , sepsis and death have all been reported ( murray and wooltorton , 2005 ; goldstone et al . , 2012 ) .
the recommendation from the royal australian and newzealand college of obstetricians and gynaecologists ( ranzcog , 2012 ) is that  medical termination should not be performed in an isolated or an inaccessible setting which lacks ready access to suitable emergency care ( in a service accepting this responsibility ) from administration of mifepristone until termination of pregnancy is complete .
 there is still debate as to the appropriate regime for medical abortion in using mifepristone and misoprostol . according to the pi misoprostol tablets are to be administered orally .
one large systematic review has found better clinical outcomes with vaginal versus oral administration , and reduced adverse effects for vaginally versus sublingual or buccal misoprostol ( kulier et al . , 2011 ) .
the current approved dose of mifepristone is 200 mg in australia whereas a dose of 600 mg of mifepristone is approved by the food and drug administration ( fda ) for use in the usa ( creinin et al . ,
the international federation of gynecology and obstetrics ( figo ) guidelines recommend only 200 mg of mifepristone ( fandes , 2011 ) which is also supported by recent evidence ( raymond et al . , 2013 ) .
it is likely that dosing regimens will continue to be researched and further evidence will be obtained that will shape recommended dosage , frequency and route of administration at different gestations .
medical management of both early ( miscarriage ) and late pregnancy loss may be achieved with misoprostol .
its widespread use for management of first trimester miscarriage is well - supported by good quality evidence worldwide ( gomez ponce de leon et al .
unfortunately there is still little uniformity in recommended treatment regimens although there is increasing evidence that lower doses may yield good results both clinically and psychologically ( barcelo et al . , 2012 ;
misoprostol is clinically effective in management of miscarriage , has cost - benefits over other methods , and is versatile from the point of view of storage , dosing regimen and route of administration . yet
, there is a clear disparity between its approved use for abortion and its off - label use for management of miscarriage .
the physiological and pharmacological mechanisms involved in both these circumstances can be assumed to be directly comparable but for the purpose of approved use of misoprostol they are viewed differently .
this raises a number of issues when dealing with women presenting with first trimester miscarriage for whom medical management is a preferred option .
off - label prescribing requires the clinician to inform the woman that her prescription is not for an approved indication as listed on the pi / cmi . the rationale for treatment with misoprostol
should be explained with reference to the evidence available to reassure her of the safety and applicability of this treatment modality ( gazarian et al . , 2006 ) .
adverse effects and further information from the pi / cmi for misoprostol may be discussed , noting that that information is specifically applicable to termination of pregnancy but being inferred for her situation .
this properly informed woman might then question the reason she may incur a non- subsidised fee for misoprostol whereas someone seeking a termination need not .
she may also become hesitant to undertake medical management due to this personal cost and questions about something called  off - label  treatment .
instigation of management with misoprostol should commence as soon as 
 reasonable given the clinical and emotional circumstances surrounding the miscarriage .
a delay in medical management has been shown to result in significantly increased emergency department presentations and need for emergency surgical management ( torre et al . , 2012 ) .
she may also decide not to undergo medical management at all and instead opt for surgical management .
the may place an increased burden on the healthcare system given the lower cost of medical versus surgical management in circumstances such as incomplete or inevitable miscarriage ( rausch et al . , 2012 ) , as well as an increased risk of preterm birth in subsequent pregnancies ( lemmers et al . , 2016 ) .
clinicians , too , should be cautious when managing first trimester miscarriage with misoprostol . since there are no formal guidelines in place , care
must be taken when prescribing off - label to select a robust protocol that is supported with good evidence ( creinin et al . , 2006 ) .
public hospitals should have in place protocols approved at local and district levels , if not by state - wide policy if possible .
private clinicians or organisations should also have a credible system available that would withstand peer - review and legal challenge .
deviation from evidence - based regimens may leave the clinician and institution open to medicolegal challenge in the case of an adverse outcome or event .
the utility of misoprostol is not being questioned since it has great applicability in gynaecology in the australian setting ( krishnan et al . , 2014 ) .
the subtleties regarding indicated versus off - label use of misoprostol , however , must be given due attention given the transparency and evidence - based requirements in modern obstetrics and gynaecology .
 clinical use of drugs is approved for specified clinical indication , route of administration , dose and population group . 
 off - label prescribing of a registered medicine occurs outside of these parameters and may be justified by pharmacology and physiology , as well as sufficient evidence from published clinical trials and reviews . 
 misoprostol and mifepristone in combination have recently been registered in australia for medical termination of pregnancy in women of child - bearing age . 
 there is good clinical evidence for efficacy and safety of misoprostol in uterine evacuation in both miscarriage and termination of pregnancy . 
 the pharmacological effects of misoprostol on the uterus and clinical outcomes in both early miscarriage and abortion are comparable . 
 medical management of miscarriage with misoprostol in australia is performed off - label . a woman presenting with first trimester miscarriage 
 must be clearly informed that use of misoprostol in her case is for a non - approved indication . 
 this raises the issue of inequity in her management compared with that of first trimester medical abortion , including being treated off - label and the potential cost of non - subsidised medication 
 . the clinician must also be careful to use an evidence - based protocol that would withstand medicolegal challenge in the case of an adverse outcome . 