Misoprostol

In Reproductive Health An Evidence Based View

Sources of Evidence
Pub Med

Cochrane library
Misoprostol Clinical Guideline WHO

Bellagio, Italy in Feb 2007 (consensus

papers )

Misoprostol Recommended dosages

(FIGO October 2009)

Misoprostol :Topics
Misoprostol An off label drug Pharmacokinetic Profiles

Misoprostol Clinical Guideline

(WHO 2007) & Recommended Dosages (FIGO 2009)

Misoprostol Is An

Off Label Drug

Misoprostol was registered in

1986 for the prevention and treatment of peptic ulcers

resulted from NSAID.

It is safe and well tolerated within the recommended dose of 800 g/day.

Misoprostol is an off label drug

As misoprostol is not registered for reproductive health indications

off label drug the industry has

neither provided the drug information for physicians nor packaged the drug in appropriate dosages.

Misoprostol Is Widely Used As Off Label Drug

It is widely used for softening the cervix and
for initiating uterine contractility

Why?
It has an effect the best available PGs Inexpensive. Stable at room temperature.

Misoprostol Is Widely Used For Reproductive Health

In a survey at: Brazil, Jamaica & USA, it was used for: IUFD in 61% Missed abortion in 57% Induction of labour in 46%
Clark et al Int J Gynecol Obstet 2002; 76:6574

The result is that misoprostol is used

in many different ways according to informal local protocols with high liability for complication.

So an evidence based guidelines for optimal misoprostol dosages is mandatory

The principles of the guideline

was based on the

pharmacokinetic profiles of
the misoprostol

Misoprostol Clinical Guideline

WHO Recommendations Bellagio,
Italy in Feb 2007

2009

Pharmacokinetic Profiles Of Misoprostol

Misoprostol is a synthetic PGE1 analogue

15

16

PG E1
1

16
15

Misoprostol is (15-deoxy-16-hydroxy-16-methyl PGE1)

Misoprostol
(Cytotec, Mesotac,Misoprost )

It is rapidly absorbed from various routes:

Oral, vaginal, cervical: As PGE2 Sublingual, rectal, & buccal.

This curve determines the dose

Safe Single Doses Of Vaginal Misoprostol

For the first trimester 800g can be safely used. In the second trimester 200g After 24 weeks 25g 6 hourly is usually used. Higher dose: Uter.hyperstimulation & rupture or F. distress

This curve determines the rout Sublingual

2-The mean time to peak levels Oral

Vaginal

1- The peak concentration

3-The Area under the curve

Time (minutes) Mean plasma concentrations of misoprostol acid over time.. Tang et al :Human Reproduction, Vol. 17, No. 2, 332-336, February 2002

Pharmacokinetic Profiles: Key Facts

Route Oral * Onset of action 8 min Duration of action 2 h 3 h

Sublingual 11 min

Vaginal
Rectal

20 min
100 min

4 h
4 h

* After oral administration, uterine tonus develops, which is not

followed by uterine contractions,unless repeated doses are given

Tang et al., Int J Gynecol Obstet (2007) 99, S160S167

Misoprostol
Side effects
Mild Diarrhea, Vomiting, Abdominal pain, Fever, Shivering 5-60% Uterine contractile abnormalities: Fetal: Distress & its sequels. Maternal: Uterine rupture & bleeding

Teratogenesis: After failed abortion

Mbius Syndrome After Misoprostol Elective Abortion Failure.

The critical period for the development of Mbius syndrome following teratogen exposure appears to be 5-8 w gestation

A child with oromandibular-limb hypogenesis-Mbius syndrome. Notice the expressionless face (due to bilateral VII nerve palsies) and missing fingers
Bos- Thompson, Ann Pharmacother. 2008 Jun;42(6):888-92.

What The Is Relative Risk Of Malformations?

While the relative risk of malformations appears real, epidemiological studies indicate that the absolute risk is low It is < 10 malformations per 1,000 births exposed to misoprostol in utero ( i e <1% )
Philip et al ,Report of a Meeting at the Population Council, New York22 May 2002

Misoprostol Clinical Guideline

WHO Recommendations Bellagio, Italy in Feb 2007 &FIGO 10-2009

2009

Misoprostol Clinical Guidelines

Cervical priming prior to transcervical procedures. Termination of pregnancy up to 12 W living pregnancy Termination of pregnancy with a live fetus at 13 to 26 W Missed abortion in the first trimester Incomplete abortion and miscarriage

Intrauterine fetal death

Induction of labor with a live fetus Prevention of postpartum hemorrhage Treatment of postpartum hemorrhage WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Fiala et al., Int J Gynecol Obstet(2007) 99 (supp 2):S168-71.

Cervical priming Prior to :

Hysteroscopy Surgical uterine evacuation

Intrauterine device insertion

The first choice recommended dosage:

400 g vaginally or sublingually 3hrs before the procedure

Advantage :
Shorter operation time Reduced blood loss Easier mechanical dilatation
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Fiala et al., Int J Gynecol Obstet(2007) 99 (supp 2):S168-71. FIGO October 2009

First Trimester Up To 12 Weeks

1st Trimester Induced Abortion up to 12 weeks

The first choice recommended dosage:

800 g vaginally 12-hourly x3

The second choice recommended dosage:

800 g sublingually 3-hourly x3(side effect)?

Ideally used 48h after mifepristone 200mg
Success rate: around 90% (less for 10-12 w)
Within 12 h: 70% - Within 24 h 80% - Within 48 h 95%
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Fandes et al., Int J Gynecol Obstet(2007) 99, S172S177 FIGO October 2009

Missed Abortion Up to 12 weeks

The first choice recommended dosage:

800 g vaginally 3-hourly x2

The second choice recommended dosage:

600 g sublingually 3-hourly x2

Versus Vacum ?

Leave to work for 1-2 weeks (unless heavy bleeding or infection)

WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gemzell-Danielsson et al., Int J Gynecol Obstet(2007) 99, S182S185

FIGO October 2009

1st Trimester Incomplete Abortion (0-12 Weeks)

The first choice recommended dosage:

600 g orally, single dose

The second choice recommended dosage:

400 g sublingually , single dose

Leave to work for 1-2 weeks (unless heavy bleeding or infection)
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Blum et al., Int J Gynecol Obstet(2007) 99, supp 2):S186-9. FIGO October 2009

Seconded Trimester 12 - 26 Weeks

Termination Of A Live nd Trimester Fetus At 2 13 To 26 Weeks

A-Termination At 13-22 Weeks

:The first choice recommended dosage: 400 g vaginally 3-hourly (x5) 200 g only for cases with previous CS If contractions is >3 contractions / 10 minutes reduce frequency (4-6 hourly)
Ideally used 48h after mifepristone 200mg
Successes: 80-90% of the women will abort within 24 h
WHO Clinical Guidelines Bellagio, Italy in Feb 2007
Blumenthal et al., Int J Gynecol Obstet(2007) 99, (supp 2):S178-81.

B-Termination At 23-26 Weeks

No adequate data for recommendations:

the dosage and frequency :

? 200 g vaginally 6-hourly (x5)
The placenta:If not delivered within 2 hours, a 10 units oxytocin in
500ml saline 20-30 drops/min ,if not delivered :Evacuation ABO & Rh blood grouping

WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Blumenthal et al., Int J Gynecol Obstet(2007) 99, (supp 2):S178-81.

Termination of Death (IUFD) 13-26 Weeks

WHO Clinical Guidelines Bellagio, Italy in Feb 2007

Missed Abortion 16 weeks

A 32 years old woman 4th gravida 3rd Para Last delivery was CS 3 years ago IUFD 16 weeks. Failed 3 trial oxytocin induction within the last 15 days

What Is The Appropriate Management ?

Other Oxytocin trial after 3-7 d
Hysterotomy Vaginal misoprostol

Dilatation &Evacuation .

What Is The Incidence of Uterine Rupture With Previous CS ?

The risk of uterine rupture
is < 0.3%. This may be acceptable to both patients and providers.
Goyal, Obstet Gynecol. 2009 May;113(5):1117-23. . A systematic review.

IUFD 13-17 Weeks

Recommended Dosages

200 g g vaginally 6-hourly (x4)

If no effective contractions with the first dose,

double to 400 mcg.

The maximum daily dosing should not exceed 1600 mcg Halve dose if previous CS with close monitor
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

IUFD 18-26 Weeks

Recommended Dosages

100 g g vaginally 6-hourly (x4)

If no effective contractions with the first dose ,

double to 200 mcg.

The maximum daily dosing should not exceed 800 mcg Halve dose if previous CS with close monitor
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

Third Trimester 27- 43 Weeks

Misoprostol For Induction Of Labor With A Live Fetus

Recommended Dosages
25 g vaginally 4-hourly (max x6),

50 g orally 4-hourly (max x6)or

20 g of oral solution 2-hourly (max x12)
There is no evidence that any one is better than the other

Do not use if previous CS :Uterine rupture 1.2-10%

WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

Sublingual Versus Vaginal Misoprostol : Induction Of Labour

The sublingual route of administration is as effective as the vaginal route. However, the safety, adverse effects, optimal dose and peri-natal outcome remain to be established It cannot be recommended for routine use in obstetric practice.
Souza et al, BJOG 2008;115:13401349. A systematic review.

Misoprostol Vaginal Tablet

Prostokos - 25g vaginal tablets, Brazil Vagiprost - 25g vaginal tablets, Egypt

. In the pipeline:
Isprelor - 25g vaginal tablets, UK

Misoprostol For Induction Of Labor With A Live Fetus

1-Prior to starting the induction :
Admission to the hospital Exclude fetal compromise (Clinical ,U/S & CTG for 30 m) Exclude: > Para 4, mal-presentation, large baby*

2-After each dose: A 30 m monitoring of:

FHR and uterine activity ( CTG) Maternal vital signs .
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190. : : ACOG 2002

Misoprostol For Induction Of Labor With A Live Fetus

3- From the onset of uterine contractions: Monitoring FHR &uterine activity and maternal vital signs/ 30 minutes . 4-At 3 regular uterine contractions / 10 miutes: No further doses of misoprostol Oxytocin infusion (if needed) :Only after 4 h of the last vaginal dose or 2h after the last oral dose of misoprostol. 4-If the cervix remains unfavorable after 24H: switching to: Alternative method, repeat course of misoprostol, or CS
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

Misoprostol For Induction Of Labor With A Live Fetus

These regimens can be used with ruptured or intact membranes. Care is needed as progress is rapid in Favorable cervix

Ruptured membranes.
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

IUFD >26 Weeks

Recommended Dosages

25-50 g g vaginally 4-hourly (x6)

If no effective contractions with the first dose , double the dose to 50-100 mcg. The maximum daily dosing should not exceed 600 mcg
If no expulsion after 24 hours, repeat at a second time. Oxytocin if necessary: 4 hours after last dose

Do not use if previous CS :Uterine rupture 1.2-10%

WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

Intrauterine Fetal Death 13-42 Weeks

Recommended Dosages
13-17 W: 200 g g vaginally 6-hourly (x4) 18-26 W: 100 g g vaginally 6-hourly (x4) >26 W: 25-50 g g vaginally 4-hourly (x6)

Success :75%within 24H. The remainder within

. Retention of the placenta :25%

further 24-H

WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

Postpartum Haemorrhage

Atonic Post partum Hemorrhage

A 25 years old women married for one year
30 minutes after normal vaginal delivery she developed atonic PP hemorrhage She received oxytocin & Methergin Misoprostol was decided before invasive measure

What Is The First Regimen of Choice of misoprostol?

1000 ug rectal
1000 ug sublingual 600 ug oral

1000 ug sublingual

Prevention of Postpartum Haemorrhage (management of 3rd stage)

Prophylactic oxytocics should be offered routinely in the management of the third stage of labour in all women as they reduce the risk of PPH by 60%. For women without risk factors for PPH delivering vaginally, oxytocin (5 iu or 10 iu by intramuscular injection) is the agent of choice for prophylaxis in the third stage of labour.
Grade A

RCOG Green-top Guideline No. 52May 2009

Prevention of PP Haemorrhage (Management of 3rd stage)

Vaginal delivery:

Grade A

Oxytocin :5 iu or 10 iu IM is the agent of choice.

CS:

Grade C

Oxytocin :5 iu by slow IV injection RCOG Green-top Guideline No. 52May 2009

Misoprostol For Prevention of Postpartum Haemorrhage

Recommended Dosages
600 g orally or sublingually
Where injectible conventional uterotonics are not available.
Second dose (for continued atonic hemorrhage): preferably 2 h after the original dose or 6 h if there is pyrexia or marked shivering . WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190. FIGO October 2009

Misoprostol For Treatment of Postpartum Haemorrhage

Recommended Dosages
600 g orally or sublingually.
Misoprostol should be used only after the provider has exhausted all standard PPH treatments (oxytocin drip, uterine massage, and/or compression).

All potential causes for PPH should be explored to assure that the PPH is not due to another factor besides uterine atony.
WHO Clinical Guidelines Bellagio, Italy in Feb 2007 Gmez Ponce de Len et al., Int J Gynecol Obstet(2007) 99, (supp 2):S190.

Conclusions

Misoprostol Recommended Dosages

2007

dose if previous CS

Misoprostol Recommended Dosages

2007

dose if previous CS