application for inclusion on who model list of essential medicines

The Secretary of the Expert Committee on the Selection and Use of Essential Medicines Medicine Access and Rational Use (MAR) Department of Essential Medicines and Pharmaceutical Policies (EMP) World Health Organization 20 Avenue Appia, CH-1211 Geneva 27, Switzerland Email: [email protected] November 30, 2012 Dear Committee Members: We are pleased to submit this application requesting that misoprostol be listed for its postpartum hemorrhage (PPH) treatment indication on the WHO’s Model List of Essential Medicines (EML) in section 22.01.00.00 “Oxytocics.” PPH continues to account for nearly one quarter of maternal deaths annually. Misoprostol, a prostaglandin E1 analogue, has been shown to induce uterine contractions and control postpartum bleeding due to uterine atony. In 2010, two large double-blind randomized controlled trials (undertaken by the group submitting this application) compared misoprostol to oxytocin for treatment of PPH due to uterine atony. The data from these studies shows that 800 mcg sublingual misoprostol stops post-partum bleeding within 20 min of its administration for nine out of ten women suffering a hemorrhage (Winikoff et al 2010; Blum et al, 2010). The World Health Organization (WHO) and the International Federation of Gynecologists and Obstetricians (FIGO) have recently updated their guidelines to reflect the current evidence-base and now endorse the use of misoprostol for PPH treatment in some circumstances. The WHO guidelines indicate that in settings where IV oxytocin is unavailable, a prostaglandin (including 800 μg sublingual misoprostol) can be used. FIGO’s guidelines state that 800 μg sublingual misoprostol is a safe and effective treatment for PPH due to uterine atony. FIGO has also called upon national regulatory agencies and policy makers to approve misoprostol for PPH prevention and treatment and to ensure that current evidence-based regimens are adopted. Inclusion of misoprostol, an evidence-based alternative to oxytocin, for its specific PPH treatment indication on the WHO Model List of Essential Medicines will bolster the package of interventions available to treat PPH. Furthermore, it will help harmonize the Model List of Essential Medicines with the WHO Guidelines on Prevention and Treatment of Postpartum Hemorrhage. We thank you for considering the addition of misoprostol to the Model List of Essential Medicines for this indication. Sincerely, Jennifer Blum Jill Durocher Dina Abbas

19th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2012

PROPOSAL FOR THE INCLUSION OF MISOPROSTOL IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES

Submitted on behalf of: Gynuity Health Projects, NY, USA Jennifer Blum, MPH Jill Durocher Dina Abbas, MPH Director Senior Program Associate Program Research Coordinator [email protected]

[email protected] [email protected]

Gynuity Health Projects 15 East 26th Street, Suite 801

New York, NY 10010 Tel: (1) 212-448-1230 Fax: (1) 212-448-1260

mailto:[email protected]

of 37

Table of Contents 1. Summary Statement of the proposal for inclusion, change or deletion .................................. 3 2. Name of the focal point in WHO submitting or supporting the application ........................... 4 3. Name of organization(s) consulted and/or supporting the application ................................... 4 4. International Nonproprietary Name (INN, generic name) of the medicine ............................ 4 5. Formulation proposed for inclusion; including adult and pediatric (if appropriate) .............. 4 6. International availability – sources, if possible manufacturers ............................................... 4 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group ............................................................................................................................................... 4 8. Information support the public health relevance .................................................................... 5

8.1 Disease Burden ..................................................................................................................... 5 8.2 Treatment of PPH ................................................................................................................. 7 8.3 Assessment of Current Use ................................................................................................... 9 8.4 Target Population .................................................................................................................. 9

9. Treatment details ..................................................................................................................... 9 9.1 Dosage Regimen and duration .............................................................................................. 9 9.2 Reference to Existing WHO and Other Clinical Guidelines .............................................. 10

10. Summary of comparative effectiveness in a variety of clinical settings ............................ 11 10.1 Randomized controlled trials testing the effect of misoprostol to treat PPH ............. 14

11. Summary of comparative evidence on safety .................................................................... 18 11.1 Side effects after misoprostol............................................................................................ 18 11.2 Misoprostol and breastfeeding ......................................................................................... 23 11.3 Misoprostol and maternal mortality .................................................................................. 24

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group .................................................................................. 24

12.1 Range of Costs for the Proposed Medicine....................................................................... 24 12.2 Comparative Cost-Effectiveness ....................................................................................... 25

13. Comparative Cost-Effectiveness – Summary .................................................................... 26 14. Summary of regulatory status of the medicine .................................................................. 26 15. Availability of pharmacopoeial standards ......................................................................... 26 16. Proposed text for the WHO model formulary .................................................................... 26 17. References .......................................................................................................................... 27 18. Appendix A – Partial List of Misoprostol Trade Names ................................................... 35

of 37

List of Tables and Figures Table 1. Estimates of maternal mortality ratio Table 2. Joint distribution of causes of maternal deaths, by region Table 3. List of selected clinical guidelines on misoprostol for PPH treatment Table 4. Treatment of PPH with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind, randomised, non-inferiority trial (Winikoff et al. 2010) Table 5. Treatment of post-partum PPH with sublingual misoprostol versus oxytocin in women receiving prophylactic oxytocin: a double-blind, randomised, non-inferiority trial (Blum et al. 2010 Table 6. Misoprostol as an adjunct to standard uterotonics for treatment of PPH: a multicentre, double-blind randomised trial (Widmer et al. 2010) Table 7. Misoprostol for treating PPH: a randomized controlled trial (Hofmeyr et al. 2004) Table 8. Misoprostol in the treatment of PPH in addition to routine management: a placebo randomised controlled trial (Walraven et al. 2004) Table 9. Misoprostol in addition to routine treatment of PPH: A hospital-based randomized-controlled trial in Karachi, Pakistan (Zuberi et al. 2008) Table 10. Case reports and observational studies on misoprostol for PPH treatment Table 11. Comparison of PPH treatment outcomes with 600 and 800 mcg sublingual misoprostol in women receiving prophylactic oxytocin (León et al 2012; Blum et al, 2010) Table 12. Rates of shivering and fever following first-line PPH treatment with 800 mcg regimen of sublingual misoprostol Table 13. Rates of shivering and fever following treatment with an adjunct dose of sublingual misoprostol (600 mcg) Table 14. Comparison of reported side effects (by provider) among Ecuadorian women given PPH treatment with sublingual misoprostol (600 mcg and 800 mcg) (León et al, 2012) Table 15. Comparison of reports of shivering and fever by Ecuadorian women during their exit interview and their perceived level of severity (600 mcg and 800 mcg) (Durocher et al, unpublished; León et al 2012) Table 16. Supplier price information (in US$) Table 17. Buyer Prices (USD) for 200 mcg Misoprostol Tablets Figure 1. Mean misoprostol plasma concentrations after sublingual administration of misoprostol (800 micrograms), and mean temperatures over time of 58 cases of high fever following treatment with 800 mcg sublingual misoprostol in Quito, Ecuador (Durocher et al, 2010)

of 37

1. Summary Statement of the proposal for inclusion, change or deletion The data presented in the following report show that misoprostol is a safe, effective and low cost treatment of postpartum hemorrhage (PPH) attributable to uterine atony. Based on results from a series of randomized clinical trials showing that misoprostol effectively controls excessive bleeding postpartum, we propose that the medicine be specifically listed for its PPH indication in section 22.01.00.00 “Oxytocics” of the WHO List of Essential Medicines (EML) list. Misoprostol is already included on the WHO Model List of Essential Medicines (22.1 Oxytocics) because of its proven safety and efficacy for medical abortion (following mifepristone), the prevention of postpartum hemorrhage, management of incomplete abortion/miscarriage and induction of labor. Presently, the World Health Organization (WHO) recommends administration of misoprostol for PPH prevention in settings where a skilled birth attendant is not present or if oxytocin is not available. However while uterotonics reduce blood loss after delivery, some woman who receive a prophylactic uterotonic following delivery will go on to experience a PPH and require treatment. To this end, in its 2012 recommendations on the Prevention and Treatment of Postpartum Hemorrhage, the WHO noted: “Intravenous oxytocin is the recommended uterotonic drug for the treatment of PPH; however, in settings where IV oxytocin is not available, or if the bleeding does not respond to oxytocin, the use of intravenous ergometrine, oxytocin-ergometrine fixed dose, or a prostaglandin drug (including sublingual misoprostol, 800 μg) is recommended.” This echoes an earlier WHO recommendation that misoprostol could be useful for PPH treatment in places where traditional injectable uterotonics are not available and/or feasible (WHO guidelines for the management of postpartum haemorrhage and retained placenta. 2009). The International Federation of Gynecologists and Obstetricians (FIGO) has also highlighted the important role of misoprostol in treating postpartum hemorrhage in their 2012 recommendations. Inclusion of misoprostol for its specific PPH treatment indication on the WHO Model List of Essential Medicines will bolster the package of interventions available to providers seeking to treat this condition and improve access to comprehensive PPH care. This proposal is based on the following evidence and considerations, described in detail below: 1. Postpartum hemorrhage is one of the largest contributors to maternal morbidity and mortality in low resource countries and accounts for nearly one quarter of all maternal deaths worldwide. Inclusion of misoprostol on the EML for its PPH treatment indication could contribute to efforts to achieve Millennium Development Goal #5 to reduce maternal mortality by three-quarters by the year 2015. 2. 800 mcg sublingual misoprostol is an easy-to-use evidence-based regimen that can be used by providers in situations in which intravenous oxytocin is not feasible.

of 37

3. Inclusion of misoprostol for its PPH treatment indication on the EML would help harmonize the Model List of Essential Medicines with the WHO Guidelines on Prevention and Treatment of Postpartum Hemorrhage. 4. In its 2012 PPH recommendations, FIGO called upon national regulatory agencies and policy makers to approve misoprostol for PPH prevention and treatment (FIGO 2012). 5. Misoprostol is safe. Side effects, when they occur, are transitory and can be easily managed by providers trained to recognize and manage them (Durocher, et al 2010). In the context of having a PPH, the benefit of having a treatment such as misoprostol outweighs the risks associated with short-lived side effects.

2. Name of the focal point in WHO submitting or supporting the application João Paulo Souza, MD, PhD, Department of Reproductive Health and Research Matthews Mathai, MD, Department of Making Pregnancy Safer

3. Name of organization(s) consulted and/or supporting the application Gynuity Health Projects, New York, USA

4. International Nonproprietary Name (INN, generic name) of the medicine The International Nonproprietary Name Modified (INNM) of the medicine is misoprostol

5. Formulation proposed for inclusion; including adult and pediatric (if appropriate) 200 mcg oral tablets 100 mcg oral tablets

6. International availability – sources, if possible manufacturers Misoprostol is widely available throughout the world, and has been available in generic formulation for several years. The first patent was granted in the United States, to Searle (now Pfizer), for marketing of Cytotec®, which continues to be the most widely distributed misoprostol tablet. The drug has been off-patent for several years and is currently manufactured by companies worldwide as shown in Appendix A.

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

We request that misoprostol be listed as an individual medicine with multiple therapeutic uses in obstetrics and gynecology. Misoprostol is already included on the WHO Model List of Essential Medicines (22.1 Oxytocic) because of its proven safety and efficacy for early medical abortion (with mifepristone), prevention of postpartum hemorrhage, management of incomplete abortion/miscarriage and induction of labor.

of 37

8. Information support the public health relevance

8.1 Disease Burden

It is estimated that in 2008 more than 350,000 women died due to complications of pregnancy and childbirth (Table 1) (UNFPA, 2010). The burden of maternal mortality falls most heavily on low resource countries where 99% of maternal deaths occur. Hemorrhage accounts for over one quarter of these maternal deaths making it the leading cause of death among women, and main causes of maternal mortality globally (Mousa and Walkinshaw 2001). As shown on Table 8.2, a systematic review of studies documenting causes of maternal death, found that hemorrhage was the leading cause of death in Africa and Asia (> 30% of deaths) (Table 2, Khan et al 2006). The risk of dying from PPH is 100 times higher in developing countries than in developed countries (Ramanathan and Arljumaran 2006). This disparity is largely attributable to the greater likelihood of deliveries unattended by trained personnel, limited access to uterotonic drugs, and geographic isolation in many low resource settings. Maternal deaths due to postpartum hemorrhage often involve delays in diagnosing heavy blood loss requiring further care and subsequent delays in seeking and arranging for this care. Furthermore, wide variation in the rates of PPH among regions of the world suggests that many regions lack resources to prevent and manage hemorrhage (Carroli 2008). PPH is also a largely unpredictable condition following childbirth. Two-thirds of PPH cases occur in women with no known risk factors, and, for the most part, referral to higher levels of care does not occur until after a PPH has been diagnosed. Furthermore, there are no known risk factors to predict which women will continue to bleed (i.e. non-responders) following first-line treatment with conventional uterotonics (Mousa 2008). Given that the average time to death from onset of PPH is two hours (Maine 1993), it is important that delivery care attendants have access to a package of interventions that can be used to treat PPH. Aside from its association with maternal mortality, PPH is also a main contributor to severe morbidity following childbirth. This is because a PPH can exacerbate existing anemia and possibly necessitate blood transfusion and surgical care with their associated risks. It is therefore critical to give providers access to all evidence-based interventions, including misoprostol, to curtail heavy bleeding following delivery. Unless we are able to effectively prevent and treat PPH in the developing world, the Millennium Development Goal #5 of reducing the maternal mortality ratio by 75 per cent by 2015 may not be reached.

of 37

Table 1. Estimates of maternal mortality ratio. (UNFPA, 2010)

of 37

Table 2. Joint distribution of causes of maternal deaths, by region. (Khan et al 2006) Table 2. Joint distribution of causes of maternal deaths, by region Developed

countries Africa Asia Latin America /

Caribbean # of maternal deaths 2823 4508 16089 11777 Number of datasets 5 8 11 10 Hemorrhage 13.4% 33.9% 30.8% 20.8% Anemia 0.0%*(0.0-0.0) 3.7% 12.8% 0.1% Hypertensive disorders 16.1% (6.7 – 24.3) 9.1%(3.9-21.9) 9.1%(2.0-34.3) 25.7% (7.9-52.4) Sepsis/infections 2.1% (0.0-5.9) 9.7%(6.3-12.6) 11.6%(0.0-13.0) 7.7%(0.0-15.1) Abortion 8.2%(0.0-48.6) 3.9%(0.0-23.8) 5.7%(0.0-13.0) 12.0% (0.0-32.9%) Obstructed labor 0.0%*(0.0-0.0) 4.1%(0.0-10.3) 9.4%(0.0-12.0) 13.4%(0.0-38.9) HIV/AIDS 0.0%*(0.0-0.0) 6.2%(0.0-13.3) 0.0%*(0.0-0.0) 0.0%*(0.0-0.0) Ectopic pregnancy 4.9%(0.4-7.4) 0.5%(0.0-3.3) 0.1%(0.0-3.9) 0.5%(0.0-4.5) Embolism 14.9%(0.0-21.2) 2.0%(0.0-5.6) 0.4%(0.0-51.0) 0.6%(0.0-8.4) Other direct causes 21.3%(0.0-33.9) 4.9%(0.0-10.3) 1.6%(0.0-25.9) 3.8% (0.0-27.9) Other indirect causes 14.4%(0.0-51.2) 16.7%(9.1-29.3) 12.5%(0.0-29.2) 3.9%(0.0-25.3) Unclassified deaths 4.8%(0.0-22.9) 5.4%(0.0-21.8) 6.1%(0.0-16.2) 11.7%(0.0-20.4) Data are pooled into percentages (range), unless otherwise. *zero indicates that the condition is not reported as a cause of death. Deaths from that cause could have occurred but listed under other or unclassified deaths. Khan et al 2006

8.2 Treatment of PPH

Uterine atony, or failure of the uterus to contract after delivery, is the most common cause of PPH and accounts for 90% of PPH cases in most countries (Mousa and Walkinshaw 2001; Carroli et al 2008). Prophylactic uterotonics has proven to reduce the proportion of women who experience PPH. However among women who have received a uterotonic to prevent postpartum hemorrhage, approximately 7% women are still at risk of developing a PPH (Carroli et al 2008). Therefore while uterotonics reduce blood loss after delivery; they do not eliminate the need to treat some women for excessive blood loss/PPH. Treatment of postpartum hemorrhage suspected to be due to uterine atony typically includes administration of an uterotonic drug (generally oxytocin and/or ergometrine), uterine massage and bimanual compression. Oxytocin, administered intravenously, is recommended to treat PPH because it is safe and highly effective and free of the side effects associated with other uterotonics, such as ergometrine (WHO 2012; Mousa, et al. 2007). Uterotonic management of PPH due to uterine atony is critical because, when successful, it avoids recourse to other, more

of 37

sophisticated interventions, including administration of intravenous fluids, additional drug therapy and/or blood transfusion and/or surgical intervention. Oxytocin administered intravenously works very well to stop postpartum bleeding. Yet, its intravenous administration requires skilled providers equipped with necessary instruments and tools to ensure proper and timely care. Given that occurrence of PPH is rare and thus the need to place an IV line at a moment’s notice is infrequent, providers outside of large tertiary level hospitals may lack the skills and confidence to do so. Furthermore, both oxytocin and injectable ergometrine require cool storage conditions for optimal use. Recent interest has focused particularly on quality of oxytocic products in field conditions. For instance, in a study by Stanton et al, 89% of the oxytocin ampoules tested did not meet the specifications for active ingredient (Stanton et al 2012). The mean percentage of active ingredient amount the oxytocin products tested was 64%; with only 26% being with the British Pharmacopoeia specifications for active ingredient. Poor storage and other field conditions mean that provision of intravenous oxytocin may not be feasible outside of the highest levels of the health care system. In South Asia and Sub-Saharan Africa, for instance, where the maternal mortality ratio (MMR) are particularly high (UNFPA 2010), alternative treatment options are needed to address the public health problem posed by PPH. Misoprostol, an E1 prostaglandin analog, has been extensively studied for a number of gynecological and obstetric indications. Unlike other prostaglandins, it is relatively inexpensive and is stable at room temperature, making it a useful medicine in settings where injectable uterotonics are not yet available and/or feasible and/or sustainable. Seven randomized controlled trials have studied postpartum administration of misoprostol for treatment of PPH (tables 5-10 and Lokugumage et al 2010 (table not shown)). Of these trials, three compared misoprostol to standard uterotonics and four tested adjunct use of misoprostol with standard uterotonics for PPH treatment. The two largest multi-center, large-scale double-blinded, placebo-controlled, randomized trials compared the effectiveness, safety, and acceptability of 800 mcg sublingual misoprostol to 40 IU intravenous oxytocin among 1,786 women diagnosed with PPH after vaginal delivery due to suspected uterine atony. The data show misoprostol to be similar in effectiveness to IV oxytocin for treatment of primary PPH in women receiving prophylactic oxytocin; however, oxytocin was found to work significantly better than misoprostol when used for PPH treatment among women who did not receive prophylactic uterotonics. In both trials, whether treatment was with oxytocin or misoprostol, nine out of ten women had their bleeding successfully controlled within 20 min of drug administration (Blum, et al. 2010; Winikoff, et al. 2010). In addition, as shown in table 10, seven case reports (treating 82 women), one open-label one arm trial and one ecological community-based study have also documented the usefulness of misoprostol for treatment of PPH. Intravenous oxytocin should be used when available, but misoprostol could be an effective alternative in settings in which IV oxytocin is not feasible. Studies have shown these side effects to be tolerable and transient with a range of doses and routes of administration. In settings such as South Asia and Sub-Saharan Africa where maternal mortality is 280 and 640 per 100,000, respectively and where PPH (>30%) is leading cause of death, misoprostol’s therapeutic effect should outweigh the possible discomfort and alarm caused by any side effects.

of 37

8.3 Assessment of Current Use

Although intravenous oxytocin is the uterotonic regimen of choice for treatment of PPH, its routine use for this indication is complicated by the need for cool storage, sterile equipment, and skilled personnel - all requirements for its optimal administration. To better combat PPH in settings where cool storage and properly equipped skilled personnel are not always available, providers have sought alternative and additional ways to treat this condition. Misoprostol has long been considered a promising medicine PPH treatment because of its known ability to induce uterine contractions. Indeed, the drug has entered clinical practice in settings worldwide, where providers use it in an ad hoc manner to stop postpartum bleeding. Ministries of Health, the International Federation of Gynecologists and Obstetricians and individual hospital protocols in many countries include guidance on PPH management that reference misoprostol as one remedy to stop postpartum bleeding.

8.4 Target Population

In settings where inadequate infrastructure, geographic constraints and limited access to higher level care prevent women from benefiting from quality oxytocin products that can be administered intravenously, alternative PPH management with misoprostol could positively impact maternal health outcomes after post-partum hemorrhage attributable to uterine atony. By having another treatment option, providers will be better equipped to manage PPH in the event of a stock-out of oxytocin, loss of refrigeration/spoilage of oxytocin supply and/or in the event of PPH needing treatment in the absence of a provider trained/confident in IV administration.

9. Treatment details

9.1 Dosage Regimen and duration

For PPH treatment, a single dose of 800 µg (4 tablets of 200 µg) sublingually, administered upon diagnosis of excessive postpartum bleeding suspected to be due to uterine atony, is recommended based on evidence from clinical trials available at this time (Winikoff et al 2010; Blum et al 2010; WHO 2012; FIGO 2012). The sublingual route is recommended because it is the only evidence-based regimen studied in randomized controlled trials (Winikoff et al 2010; Blum et al 2010). Further, its rapid uptake, prolonged duration, and greater bioavailability when administered sublingually (as opposed to other routes of administration) enhance its efficiency when used to treat a PPH (Hofmeyr, et al. 2005). In the studies by Winikoff and Blum, most women who were randomized to receive sublingual misoprostol for PPH treatment reported being satisfied with this route of administration. One recent study testing 600 mcg sublingual misoprostol as first-line treatment for PPH among women receiving oxytocin prophylactically provides some evidence that this dose may also be effective (see below Case Reports and Observational Studies) (León 2012. First-line treatment with 600mcg sublingual misoprostol alone controlled PPH within 20 minutes for 82% of women (León 2012). In comparison, two large multi-country randomized controlled trials testing an 800mcg regimen of sublingual misoprostol in the presence and absence of oxytocin prophylaxis

of 37

confirmed rates of efficacy of 89.2% (363/407) and 90.2% (440/488), respectively [Blum 2010, Winikoff 2010]. Although the Ecuador trial was not powered to compare the effectiveness of the 600 mcg and 800 mcg sublingual misoprostol regimens, the lower dose worked well in controlling blood loss. There were no maternal deaths, hysterectomies, or other surgeries performed following first-line treatment with 600mcg of sublingual misoprostol. While no special diagnostic or treatment facilities and/or specialized skills are needed for provision of misoprostol for PPH treatment; all providers should be trained to recognize heavy post-partum bleeding requiring care. Furthermore, all providers should be trained to recognize and manage side effects after administration of misoprostol given reports of hyperpyrexia after 800 mcg sublingual misoprostol among post-partum women (see section below on side effects).

9.2 Reference to Existing WHO and Other Clinical Guidelines

Several large international bodies, including the WHO and FIGO, have recently updated their guidelines to reflect the current body of evidence. Additional updates are expected in the future. The following table summarizes current recommendations and guidelines from several key organizations. Table 3. List of selected clinical guidelines on misoprostol for PPH treatment Agency Guidelines WHO recommendations for the prevention and treatment of postpartum haemorrhage. 2012

PPH PREVENTION: • Oxytocin (10 IU, IV/IM) is the recommended uterotonic drug for the prevention of PPH. In settings where oxytocin is unavailable, the use of other injectable uterotonics (if appropriate ergometrine/methylergometrine or the fixed drug combination of oxytocin and ergometrine) or oral misoprostol (600 μg) is recommended. • In settings where skilled birth attendants are not present and oxytocin is unavailable, the administration of misoprostol (600 μg PO) by community health care workers and lay health workers is recommended for the prevention of PPH. PPH TREATMENT: • Intravenous oxytocin alone is the recommended uterotonic drug for the treatment of PPH. • If intravenous oxytocin is unavailable, or if the bleeding does not respond to oxytocin, the use of intravenous ergometrine, oxytocin-ergometrine fixed dose, or a prostaglandin drug (including sublingual misoprostol, 800 μg) is recommended.

International Federation of Gynecology and Obstetrics. 2012 Treatment of Post-Partum Haemorrhage with Misoprostol: FIGO Guideline

• One dose of misoprostol 800 μg sublingually is indicated for treatment of PPH when 40 IU IV oxytocin is not immediately available (irrespective of the prophylactic measures). The recommended dose does not change according to the woman’s weight.

FIGO 2012: Prevention and treatment of postpartum

• FIGO has made a call to action in which they state that all birth attendants have the necessary training—appropriate to the settings where

of 37

hemorrhage in low-resource settings offer a comprehensive overview of a combination of best practice approaches and life-saving interventions along a continuum of care from community to hospital

they work—to administer uterotonic drugs safely and ensure that uterotonics are available in sufficient quantity to meet the need. • To achieve this they call upon national regulatory agencies and policy makers to approve misoprostol for PPH prevention and treatment and to ensure that current best-evidence regimens are adopted, including the use of a single dose of misoprostol 800 μg (4×200-μg tablets) for treatment for PPH due to uterine atony. • FIGO noted that in home births without a skilled attendant, misoprostol may be the only technology available to control PPH.

Boletin de la Direccion Ejecutiva y Comites de La Federacion Latinoamericana de Sociedades de Obstetricia y Ginecologia (FLASOG). Consenso Latinoamericano sobre usos del Misoprostol en Obstetricia y Ginecologia. Articulo Central, Volumen 1, Numero 1, Mayo 2012: 4-7.

• 800 sublingual misoprostol is recommended for PPH treatment when oxytocin is not available.

Royal College of Obstetricians and Gynaecologists. Green-top Guideline No. 52. May 2009

• Misoprostol (prostaglandin E1) may be an appropriate alternative (for PPH treatment) in settings where parenteral prostaglandins are not available or where there are contraindications (usually asthma) to prostaglandin F2.

• If uterine atony perceived to be the cause of the bleeding, a series of mechanical and pharmacological measures should be instituted. Misoprostol is included in this list of possible pharmacological measures that may be utilized.

American Congress of Obstetricians and Gynecologists. Practice Bulletin No. 76. 2006

• Misoprostol is included in the list of uterotonics to be used as the first-line treatment for hemorrhage in the event of decreased uterine tone.

10. Summary of comparative effectiveness in a variety of clinical settings For over a decade, researchers have tried to determine if there is an association between postpartum administration of misoprostol and cessation of excessive blood loss. A Pub Med review of misoprostol for PPH treatment in English, Spanish or French through November 2012 found seven RCTs and nine other reports. Of the seven randomized controlled trials that have studied postpartum administration of misoprostol for treatment of PPH three compared misoprostol to standard uterotonics alone and four studied the potential adjunct effect of misoprostol when combined with standard uterotonics for PPH treatment (Winikoff et al 2010, Blum et al 2010, Widmer et al 2010, Walraven et al 2005, Hofmeyr et al 2005, Zuberi et al 2008, Lokugumage et al 2001).

http://www.acog.org/



of 37

a. Trials of misoprostol alone to treat PPH Three published RCTs assess the role of misoprostol when used alone for treatment of PPH. The two largest multi-center, large-scale double-blinded, placebo-controlled, randomized trials compared the effectiveness, safety, and acceptability of 800 mcg sublingual misoprostol to 40 IU intravenous oxytocin among 1,786 women diagnosed with PPH after vaginal delivery due to suspected uterine atony were published in January 2010 (Blum et al 2010, Winikoff et al 2010). Two trials have provided evidence that 800 mcg sublingual misoprostol is a viable alternate to treat primary postpartum hemorrhage after oxytocin prophylaxis during the third stage of labor. Among women receiving oxytocin prophylactically, misoprostol stopped bleeding as rapidly as oxytocin did and with a similar quantity of blood loss. Among women who did not receive a prophylactic uterotonic, oxytocin was significantly better at treating PPH. These findings demonstrate that, relative to oxytocin, misoprostol is also effective in controlling post-partum bleeding. In both trials, whether treatment was with oxytocin or misoprostol, nine out of ten women had their bleeding successfully controlled within 20 min of drug administration (tables 4 and 5). A trial by Lokugamage et al. (2001) reported that 800 mcg rectal misoprostol conferred a significant advantage over syntometrine and IV syntocinon for PPH treatment. Reporting on 64 women treated for postpartum hemorrhage, the authors found a 28.1% difference in the rate of bleeding cessation in 20 minutes in favor of misoprostol (p=0.01). However, the study was not blinded and blood loss was assessed visually, which may have permitted investigator bias to influence the results. b. Trials of misoprostol as adjunct PPH treatment Four RCTs and one retrospective cohort study reported on misoprostol as an adjunct to standard PPH treatments (Tables 6-9) (Walraven 2005, Hofmeyr 2005, Zuberi 2008, Barauh 2008, Widmer 2010). The initial trials (Walraven, Hofmeyr and Zuberi) were not adequately powered to detect significant differences between the misoprostol and placebo arms but all showed favorable trends in blood loss reduction in the misoprostol arms leading to calls for a larger, adequately powered trials to definitively determine the role of misoprostol as adjunct care for PPH (Hofmeyr 2004; Walraven 2004; Zuberi 2008). A trial by Widmer et al (2010) enrolled 1422 women at hospitals in five countries and randomized them to either misoprostol plus standard uterotonics or placebo plus standard uterotonics. In this trial, women in both study arms had similar rates of additional blood loss ≥500 mL at 60 min (misoprostol plus standard uterotonics: 14·2% (100/705) vs. placebo plus standard uterotonics: 14·0% (100/717)), relative risk RR 1·02 95% CI 0·79 - 1·32). Misoprostol was associated with a significantly higher incidence of shivering (misoprostol plus standard uterotonics: 64·6% (455/704) vs. placebo plus standard uterotonics: 32·1% (230/717) (RR: 2·01 95% CI 1·79 - 2·27)). These findings demonstrate that the addition of 600 µg sublingual misoprostol to conventional injectable uterotonics for PPH treatment confers no clinical advantage. Meta-analysis of blood loss ≥500 mL reported in the four trials on adjunct PPH treatment with misoprostol show a pooled risk ratio of 0·89 (95% CI 0·71-1·12) (Widmer et al 2010).

of 37

A retrospective cohort study examined data from 58 patients with PPH receiving either misoprostol or methylergonovine malaete as second line treatment (after standard oxytocics) for primary PPH (Barauh 2008). The results showed similar outcomes in terms of need for third line treatment to stop PPH (misoprostol =67%, methylergonovine malaete = 77%) and other interventions (no statistically significant differences between need for blood transfusion, third line medical treatment or surgery, data not shown). This study offers some information about possible utility of misoprostol as adjunct/second line PPH treatment, but its design introduces possible selection bias and its small number (n=58) makes it difficult to draw firm conclusions about the generalizability of the results. c. Case reports and observational studies Seven reports tested a range of misoprostol doses (200 mcg to 1000 mcg) and different routes of administration with or without other uterotonics (Mousa 2007, O’Brien P et al. 1998, Ozan H et al. 2000, Abdel-aleem H Shojai R et al. 2004, Shojai R et al. 2001, Adekanmi OA et al. 2001, Oboro VO et al. 2003) (Table 10). These studies offer little evidence to support a specific dose or dosing regimen, or of the effectiveness of misoprostol alone, as opposed to its use in conjunction with other interventions. As shown on table 11, one ecological community-based study compared referral rates in districts where misoprostol was available for PPH treatment versus those in which it was not (Prata et al. 2005). A pilot study conducted at one hospital in Quito, Ecuador (the same hospital that had participated in previous multi-country PPH treatment trial testing 800mcg dose of sublingual misoprostol (Winikoff et al 2010) tested a lower dose of sublingual misoprostol (600mcg). The purpose of the study was to determine whether the rate of misoprostol-induced side effects could be significantly reduced with a lower dose in this setting (see section 11). The study enrolled 50 women to receive first-line PPH treatment with misoprostol. Although the study was not designed to evaluate the effectiveness of the lower dose, time to bleeding cessation and measured blood loss were documented (Table 11; Leon 2012). Because the Ecuador study enrolled only women given oxytocin prophylaxis, we compared the new findings with outcome measures of clinical effectiveness from the trial by Blum et al 2010 that tested an 800 mcg dose of misoprostol among women given oxytocin prophylaxis (Table 11). There were no differences in blood loss outcomes between the two misoprostol regimens across the two studies. The 600 mcg dose of sublingual misoprostol resulted in additional blood loss ≥ 500 mL post-treatment for 10.0% (5/50) of women versus 14.2 % (58/407) among women treated with 800 mcg sublingual misoprostol in the trial by Blum et al 2010 (relative risk 0.70 95% CI 0.30-1.67). Although the sample size is small, treatment with a 600 mcg sublingual regimen of misoprostol in settings that practice routine administration of oxytocin prophylaxis appears to have promise in controlling blood loss. The lower dose of sublingual misoprostol may offer an alternative method for treating PPH in communities known to be more sensitive to the thermoregulatory side effects of misoprostol. However, the Ecuador study was not designed to provide conclusive evidence of misoprostol’s efficacy using a 600 mcg sublingual dose.

of 37

d. Summary of effectiveness from clinical trials Three reviews published in 2007 concluded that there is insufficient evidence to support misoprostol for PPH treatment (Blum 2007, Gülmezoglu et al. 2007, Mousa 2007). In 2010, data from the two published large randomized controlled trials suggested otherwise. Indeed, while oxytocin remains the gold standard for PPH treatment; the trials by Winikoff et al. 2010 and Blum et al. 2010 confirm that there is also a place for misoprostol in the management of postpartum hemorrhage. A recent expert review covering evidence from 51 randomized controlled trials for both prevention and treatment of PPH summarized the body of evidence in support of misoprostol for PPH indications (Sheldon 2012). In its recently updated guidelines, the International Federation of Gynecology and Obstetrics state that research has demonstrated that misoprostol significant reduces the need for additional interventions for PPH, and hence a dose of misoprostol 800 μg (4×200-μg tablets) administered sublingually is a safe and effective treatment for PPH due to uterine atony. The guidelines recognize that in the event that there is no skilled birth attendant present, misoprostol may be the only option available to control PPH (FIGO 2012).

While there appears to be no advantage to adjunct use of misoprostol for PPH treatment, use of misoprostol alone for PPH treatment does appear to be effective in controlling PPH. Misoprostol is thus a useful and important addition to the package of interventions seeking to address PPH due to uterine atony.

10.1 Randomized controlled trials testing the effect of misoprostol to treat PPH

Table 4. Treatment of PPH with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind, randomised, non-inferiority trial (Winikoff, et al, 2010)

Misoprostol (n = 488)

Oxytocin (n = 490)

RR (95% CI)

p-value

Active bleeding controlled within 20 min with initial uterotonic treatment

440 (90·2%) 468 (95·5%) 0·94 (0·91–0·98) 0·001

Additional blood loss ≥ 300 ml 147 (30·1%) 83 (16·9%) 1·78 (1·40–2·26) <0·001 Additional blood loss ≥ 500 53 (10·9%) 20 (4·1%) 2·84 (1·63–5·01) <0·0001 Additional blood loss ≥ 1000 5 (1·0%) 3 (0·6%) 1·67 (0·40–6·96) 0.360 Drop in Hb ≥ 2 g/dL or blood transfusion 250 (51·2%) 230 (46·9%) 1·09 (0·96–1·24) 0·101 Drop in Hb ≥ 3 g/dL or blood transfusion 199 (40·8%) 148 (30·2%) 1.35 (1·14–1·60) <0.0001 Additional uterotonics 61 (12·5%) 31 (6·3%) 1·98 (1·31–2·99) 0·001 Blood transfusion 41 (8·4%) 26 (5·3%) 1·58 (0·98–2·55) 0·036 Hysterectomy/Other surgery 0 (0·0) 0 (0·0) -- -- -- -- Maternal death 0 (0·0) 0 (0·0) -- -- -- -- Numbers are n (%) unless otherwise specified. RR = Relative Risk. Hb=Hemoglobin.

of 37

Table 5. Treatment of post-partum PPH with sublingual misoprostol versus oxytocin in women receiving prophylactic oxytocin: a double-blind, randomised, non-inferiority trial (Blum et al, 2010).

Misoprostol n = 407

Oxytocin n = 402

Relative Risk (95% CI)

p-value

Active bleeding controlled w/in 20 min. with initial uterotonic treatment

363 (89·2%) 360 (89·6%) 0·99 (0·95–1·04)

·867

Additional blood loss ≥ 300 ml after treatment

139 (34·4%) 123 (30·7%) 1·12 (0·92–1·37) ·146


58 (14·4%) 53 (13·2%) 1·09 (0·77–1·54) ·713


11 (2·7%) 3 (0·7%) 3·62 (1·02–12·89) ·062

Drop in Hb ≥ 2 g/dL or blood transfusion 152 (37·6%) 142 (35·7%) 1·06 (0·88–1·27) ·567 Drop in Hb ≥ 3 g/dL or blood transfusion 104 (25·7%) 90 (22·6%) 1·14 (0·89–1·46) ·301 Additional uterotonics 40 (9·8%) 46 (11·5%) 0·86 (0·58–1·28) ·260 Blood transfusion 24 (5·9%) 18 (4·5%) 1·32 (0·73–2·39) ·229 Hysterectomy 4 (1·0%) 2 (0·5%) 1·98 (0·36–10·73) ·350 Maternal death 1 (0·2%) 1 (0·2%) 0·99 (0·06–15·74) ·747 Numbers are n (%) unless otherwise specified. RR = Relative Risk. Hb=Hemoglobin.

of 37

10.2 Randomized-controlled trials (RCTs) testing the adjunct effect of misoprostol when used in conjunction with standard oxytocics to treat PPH Table 6. Misoprostol as an adjunct to standard uterotonics for treatment of PPH: a multicentre, double-blind randomised trial (Widmer et al, 2010).

Misoprostol+standard uterotonics

(n=705)

Placebo+standard uterotonics

(n= 717)

RR (95% CI)

Blood loss of ≥ 500 ml within 60 min after randomization

100 (14%) 100 (14%) 1.02 (0.79 to 1.32)


9 (1%) 9 (1%) 1.02 (0.41 to 2.55)


149 (21%) 162 (23%) 0.93 (0.77 to 1.14)


17 (2%) 22 (3%) 0.78 (.42 to 1.47)

Any uterotonic after randomization 188 (27%) 203 (28%) 0.94 (0.79 to 1.11) Hb Concentration of <80 g/l within 24 hour post partum or need for blood transfusion*

121 (185) 139 (20%) 0.89 (.72 to 1.11)

Blood transfusion after randomization 103 (15%) 117 (16%) 0.89 (.7 to 1.14) Maternal death 2 (<1%) 0 NA Severe morbidity 8 (1%) 10 (1%) 0.81 (0.32 to 2.00) Data are number (%) or median (IQR), unless otherwise indicated. NA=not applicable. *Data were recorded for 691 patients receiving misoprostol and 710 patients receiving placebo; outcomes could not be measured in remaining patients. †These data are median difference (95% CI). ‡Data were recorded for 703 patients receiving misoprostol and 714 patients receiving placebo; outcomes could not be measured in remaining patients. §Defined as hysterectomy or admission to a maternal intensive care unit. Table 7. Misoprostol for treating PPH: a randomized controlled trial (Hofmeyr et al, 2004).

Misoprostol+standard uterotonics

(n=117)

Placebo+standard uterotonics

(n=121)

RR/MD 95% CI

Blood loss 500ml* 6 (5.1%) 11 (9.2%) 0.56 0.21 to 1.46 Blood loss ≥ 1,000ml* 1 (0.85%) 0 (0%) -- -- 24 hour Hb < 8 g/dl or blood transfusion

43 (39%) 37 (32%) 1.23 0.86 to 1.75

Additional uterotonic after enrolment

63 (57%) 63 (56%) 1.01 0.80 to 1.27

Blood transfusion 19 (17%) 15 (13%) 1.31 0.70 to 2.45 Hysterectomy** 3 (2.6%) 0 (0%) Maternal death** 3 (2.6%) 0 (0%) RR = relative risk; MD = mean difference; Conf = confidence; SD = standard deviation *Measured, within 1 hour after enrolment ** One woman died after hysterectomy and is counted in both outcomes

of 37

Table 8. Misoprostol in the treatment of PPH in addition to routine management: a placebo randomised controlled trial (Walraven et al, 2004).

Misoprostol+ standard

uterotonics

(n=79)

Placebo+ standard

uterotonics (n= 81)

Effect size* (95% CI)

Blood loss ≥ 500 ml 13 (16.5) 23 (28.4) 0.58 (0.32 to 1.06) Blood loss ≥ 1000 ml 2 (2.5) 5 (6.2) 0.41 (0.09 to 1.77) Postpartum hb <6 g/ dl -1 or blood transfusion 12 (15.2) 12 (14.8) 1.02 (0.49 to 2.15) Hysterectomy 0 2 (2.5) - Use of additional uterotonics 3 5 (6.2) 0.62 (0.17 to 2.25) *Relative risk except for average blood loss after taking study medication. For other outcomes, the difference between means is shown. Table 9. Misoprostol in addition to routine treatment of PPH: A hospital-based randomized-controlled trial in Karachi, Pakistan (Zuberi et al, 2008).

Misoprostol+ standard

uterotonics

(n=29)

Placebo+ standard

uterotonics (n= 32)

RR (95% CI) or p-value

Blood loss ≥ 500 ml post-treatment % (n) 7.4 (2)* 12.5 (4) 0.59 [0.12, 2.99] Mean drop in Hb ± sd (range) 2.0 ± 1.1

(0.4-4.2) 2.2 ± 1.4 (0.1-5.1)

P= .614

Postpartum Hb >/ g/dl lower than pre-delivery Hb %(n)

41.4 (12) 56.3 (18) 0.74 [.43, 1.25]

Blood transfusion %(n) 17.2 (5) 18.8 (6) .92 [.31, 2.69] Referrals for additional PPH care %(n) 3.4 (1) 3.2 (1) 1.1 [.07, 16.9] *Two cases in the misoprostol arm have incomplete blood loss measurements and were excluded from analysis of measured postpartum blood loss.

of 37

Table 10. Case reports and observational studies on misoprostol for PPH treatment

Author, publication date

Misoprostol Regimen Women Enrolled

Success

O’Brien et al, 1998 1000 ug rectally 14 14/14 (100%)

Ozan et al, 2000 400 ug orally, repeated 2 hourly once or twice 2 2/2 (100%) Abdel-Aleem et al, 2001

600 ug (n=4) 1000 ug (n=14) rectally soon after other uterotonics

18 1618 (88%)

Shojai et al, 2001 200 ug rectally 5 5/5 (100%) Adekanmi et al, 2001 800 ug intrauterine + bimanual compression of uterus 1 1/1 (100%) Oboro et al, 2003 800 ug intrauterine + bimanual compression of the uterus 1 1/1 (100%) Shojai et al, 2004 1000 ug rectally 41 26/41 (63%) Prata el al, 2005 1000 ug rectally 111* 103**/111

(93%) León et al 2012 800 ug sublingually 50 48/50 (82%) *women delivering vaginally with subsequent blood loss of 500 ml or more in the intervention group ** women who did not need to be referred to higher level of care Table 11. Comparison of PPH treatment outcomes with 600 and 800 sublingual misoprostol in women receiving prophylactic oxytocin (León et al, 2012; Blum et al, 2010), n(%)

600 mcg sublingual

misoprostol (n=50)

800 mcg sublingual

misoprostol (n=407)

RR (95% CI)

Active bleeding controlled within 20 min with initial uterotonic treatment 41 (82.0)

363 (89.1) 0.92 (0.80-1.05)

Additional blood loss post-treatment 200 (100, 300) 200 (100, 300) ns Additional blood loss ≥ 300 mL post-treatment 13 (26.0) 139 (34.1) 0.76 (0.47-1.24)

Additional blood loss ≥ 500 mL post-treatment 5 (10.0)

58 (14.2) 0.70 (0.30-1.67)

Additional blood loss ≥ 1000 mL post-treatment 0 (0.0) 3 (0.7) --

11. Summary of comparative evidence on safety

11.1 Side effects after misoprostol

Women who receive misoprostol during the third stage of labor are at risk for elevated body temperature, shivering, nausea and vomiting. The most common side effects associated with the postpartum administration of misoprostol are shivering and pyrexia (Mousa et al 2007). Studies on postpartum use of misoprostol show the rates of shivering and fever to be related, and to be dose- and route-dependent (Mousa et al 2007; Hofmeyr et al 2009). Compared to placebo, a

of 37

recent meta-analysis shows that the risk of pyrexia is increased three-fold with 400 mcg misoprostol and six-fold with 600 mcg misoprostol when administered during the third stage of labor (Hofmeyr and Gülmezoglu 2008). Higher rates of shivering and elevated body temperature are also associated with oral and sublingual routes of administration, which achieve a higher and quicker maximum plasma concentration than vaginal or rectal administration (Chong et al. 2004; Tang et al. 2002; Zieman et al. 1997). One prevention trial comparing an oral misoprostol versus rectal administration of 600 mcg confirmed that the oral dose resulted in significantly higher rates of shivering (76 versus 54%) and fever (9 versus 1%) (Khan et al 2003). Moreover, reported rates of shivering and fever vary greatly in the literature (Patted et al 2009; Durocher et al 2010). For example, rates of shivering and fever following a treatment dose of sublingual misoprostol (800mcg) given sublingually range from 7 to 90% and 5 to 93%, respectively (Durocher et al 2010). A review of the literature confirms that these side effects are transient, short-lived and not life-threatening (Gülmezoglu et al 2007; Patted et al 2009; Ng et al 2001; Lumbiganon et al 2002; Durocher et al 2010). In the context of PPH, most agree that the benefits of misoprostol as a potent uterotonic outweigh the risks of experiencing these short-lived side effects (Derman et al 2006; Durocher et al 2010). Shivering and fever are common side effects following misoprostol’s use as a first-line treatment and as an adjunct therapy for PPH (see Tables 12-13). Two studies testing an 800 mcg dose of sublingual misoprostol for PPH treatment have documented rates of shivering that range from 37 to 47%, compared with a 15% rate of shivering among women given treatment with IV oxytocin (Blum et al 2010; Winikoff et al 2010). Rates of fever after treatment were also more common in the misoprostol group (34% vs. 10%, respectively) (Blum et al 2010; Winikoff et al 2010). Two studies testing a 600 mcg regimen of sublingual misoprostol versus placebo as an adjuvant therapy also report that shivering and fever occurred significantly more often among women randomized to misoprostol (Table 13) (Zuberi et al 2008; Widmer et al 2010). Lower rates of shivering and fever were documented in one study testing 600 mcg (200 mcg orally + 400 mcg sublingually) among 160 women randomized to receive either misoprostol + standard uterotonics or placebo + standard uterotonics (shivering 29% vs. 10%; fever 20% vs. 10%) (Walraven et al 2004). Furthermore, as oxytocin prophylaxis is increasingly used in hospital settings (reducing the occurrence of PPH by up to 75%), the number of women exposed to further treatment with oxytocics, including misoprostol, will be reduced, thereby minimizing exposure to side effects from these drugs. In several PPH prevention and treatment studies, misoprostol has been associated with fever greater than 40.0°C (104°F). Cases of high fever noted in the literature include five of 9198 cases reported from the largest hospital- based clinical trial on the prevention of PPH, in which a prophylactic oral dose of 600 micrograms misoprostol was used (Gulmezoglu et al. 2001). Four cases of 1026 were reported by Ng and colleagues after testing a similar regimen (Ng et al. 2001). One case was reported in 1997 by Chong et al. A PPH treatment trial in South Africa reported three women (out of 114) with temperatures of above 40.0°C following 1000 mcg misoprostol (200 mcg orally + 400 mcg sublingually + 400 mcg rectally) (Hofmeyr et al. 2004). There have been no other reports of high fever following rectal administration of misoprostol for PPH (Mousa et al 2007; Khan et al 2003). In Pakistan, one case of high fever (out of 29) following adjunct treatment with a sublingual dose of 600 mcg was reported (Zuberi et al 2007). A multi-country trial investigating the adjunct use of sublingual misoprostol (600 mcg) following

of 37

standard uterotonics for PPH treatment also documented a 7% rate of high fever above 40.0°C among 48 women (out of 704), compared with a rate of 1% among women who received standard uterotonics + placebo to treat their PPH (Widmer et al 2010). In addition, two multicentre studies testing an 800 mcg regimen of sublingual misoprostol as first-line treatment for PPH reported a higher-than-expected rate of fever above 40.0°C in one of nine sites (Quito, Ecuador: 36%; 58/163), whereas much lower rates were recorded in the other eight sites, ranging from 0% to 9% (Blum et al 2010; Winikoff et al 2010; Durocher et al 2010). In all of these hospital-based reports, the elevated temperatures did not result in further complication. A World Health Organization report on the safety profile of misoprostol for obstetrical indications reviewed all the published cases of temperature of 40 °C or higher following treatment with misoprostol for PPH. The authors commented that in all cases temperature resolved itself within several hours and without complication through management with antipyretics and cool compresses (Wannmacher L. 2010). To understand better the characteristics of fevers above 40.0°C that occurred at a higher frequency in Quito, Ecuador, systematic measures of body temperature post-treatment with 800 mcg of sublingual misoprostol were documented for 58 cases with high fever in this site (Durocher et al 2010). High fever was typically characterized by a sharp increase in temperature within 1 hour of treatment, a peak temperature 1-2 hours post-treatment, and a gradual decline in temperature over a period of 3 hours. As shown on Figure 1, the pattern of temperature elevation appears to mimic misoprostol blood concentration following sublingual administration and the fevers followed a predictable course. A study in Ecuador tested a lower dose of sublingual misoprostol (600 mcg) to determine whether the rate of fever could be reduced in this setting (León et al 2012). This study enrolled women who were given uterotonics prophylactically. Body temperature was systematically measured for 50 women diagnosed with PPH and given 600 mcg of sublingual misoprostol as first-line treatment. Rates of side effects were compared between this study and a previous one testing an 800 mcg regimen of sublingual misoprostol among women not exposed to prophylactic uterotonics (Table 14). Data on the 800 mcg sublingual regimen were collected as part of the multi-country RCT comparing treatment with misoprostol to oxytocin (Winikoff et al 2010); however, the Ecuador country-level data are currently unpublished. The incidence of high fevers (above 40.0°C) following treatment with 600 mcg sublingual misoprostol compared to previously documented rates using 800 mcg sublingual misoprostol show a 50% reduction in the rate of high fever with the lower dose (8/50; 16% vs. 58/163; 36%; relative risk 0.45 95% CI 0.23-0.88) (table 15). Only one woman had severe shivering following the 600mcg dose, compared with 19 women in the 800 mcg cohort (2% vs. 12%; relative risk 0.17 (0.02-1.25)) No cases of delirium/altered sensorium were reported. The temperature trends documented in these two studies in Ecuador provide reassurance to clinicians that misoprostol-induced fever (regardless of how high the peak temperature) are transitory.

of 37

Table 12. Rates of shivering and fever following first-line PPH treatment with 800 mcg regimen of sublingual misoprostol, n (%) Winikoff et al, 2010 (Multi-country trial)

Misoprostol n = 488

Oxytocin n = 490


Shivering 229 (46·9) 82 (16·8) 2·80 (2·25–3·49) Fever 217 (44·5) 27 (5·5) 8·07 (5·52–11·8)

Temp ≥40·0 C° 66 (13·5) 0 (0·0) -- -- Blum et al, 2010 (Multi-country trial)

Misoprostol n =407

Oxytocin n=402


Shivering 152 (37.3) 59 (14.7) 2.54 (1.95–3.32)

Fever 88 (21.6) 59 (14.7) 1.47 (1.09–1.99)

Temp ≥40·0 C° 5 (1.2) 1 (<1) 4.94 (0.58–42.09) Table 13. Rates of shivering and fever following treatment with an adjunct dose of sublingual misoprostol (600 mcg), n (%) * Widmer et al, 2010 (multi-country)

Misoprostol n=704

Placebo n=717


Shivering Any 455 (64.6) 230 (32.1) 2.01 (1.79–2.27) Severe 80 (11.4) 7 (1.0) 11.64 (5.41–25.03)

Fever ≥ 38°C 303 (43) 107 (15) 2.88 (2.37–2.5) ≥ 40°C 18 (3) 3 (<1) 6.11 (1.81–20.65)

Walraven et al, 2004 (The Gambia)

Misoprostol ^ n=79

Placebo n= 81


Shivering Any

23 (29.1)

8 (9.9)

2.95 (1.40–6.19)

Fever ≥ 37.5°C

16 (20.3)

8 (9.9)

2.05 (0.93–4.52)

Zuberi et al, 2008 (Pakistan)

Misoprostol n=29

Placebo n=32


Shivering None 14 (48.3) 30 (93.8) Mild or moderate Severe

11 (37.9) 4 (13.8)

2 (6.2) 0 (0.0)

8.28 [2.1–33.1]

Fever 48.3 (14) 41.4 (12) 10.3 (3)

90.6 (29)

9.4 (3) --

5.52 [1.8–17.1] None Mild or moderate Severe

* Misoprostol plus standard uterotonics versus placebo plus standard uterotonics. ^ Misoprostol regimen was administered as 400 mcg sublingual + 200 mcg oral.

of 37

Figure 1: Mean misoprostol plasma concentrations after sublingual administration of misoprostol (800 micrograms), and mean temperatures over time of 58 cases of high fever following treatment with 800 mcg sublingual misoprostol in Quito, Ecuador (Durocher et al, 2010)

Table 14. Comparison of reported side effects (by provider) among Ecuadorian women given PPH treatment with sublingual misoprostol (600mcg and 800mcg)^

600 mcg*

(n=50) 800 mcg**

(n=163)

RR 95% CI Any fever 44 (88.0) 151 (92.6) 0.95 (0.85-1.06) ≤ 37.9 °C 6 (12.0) 12 (7.4) 1.63 (0.64-4.12) 38.0 – 38.9 °C 23 (46.0) 32 (19.6) 2.34 (1.52-3.61) 39.0 – 39.9 °C 13 (26.0) 61 (37.4) 0.69 (0.42-1.15) ≥ 40.0 °C 8 (16.0) 58 (35.6) 0.45 (0.23-0.88) Any shivering 48 (96.0) 146 (89.6) 1.07 (0.99-1.16) Mild shivering 29 (58.0) 56 (34.4) 1.69 (1.23-2.32) Moderate shivering 18 (36.0) 71 (43.6) 0.83 (0.55-1.24) Severe shivering 1 (2.0) 19 (11.7) 0.17 (0.02-1.25) Any fainting 2 (4.0) 4 (2.5) 1.63 (0.31-8.64) Any nausea 0 (0.0) 8 (4.9) -- Any vomiting 0 (0.0) 8 (4.9) -- Any diarrhea 0 (0.0) 2 (1.2) -- Any other side effect 1 (2.0) ☼ 20 (12.3) ☼☼ 0.16 (0.02-1.18) ^Rates of side effects were compared between two separate studies testing two different regimens of misoprostol for treatment of PPH among Ecuadorian women with PPH enrolled at a maternity hospital in Quito, Ecuador. *This study enrolled Ecuadorian women exposed to uterotonics prophylactically and treated with 600 mcg sublingual misoprostol for PPH (León 2012) ** These data are taken from another study that enrolled Ecuadorian women who were not exposed to uterotonics prophylactically and treated with 800 mcg sublingual misoprostol. (These data were collected as part of a multi-country RCT (Winikoff et al 2010, country-level data not shown in publication) ☼ Other side effects: headache ☼☼ Other side effects: delirium/altered sensorium (10), headache (2), thirst (3), pain/cramping (3), excessive sweating (1), feel cold / teeth chattering (1)

of 37

Table 15. Comparison of reports of shivering and fever by Ecuadorian women during their exit interview and their perceived level of severity (600 mcg and 800 mcg)^

600 mcg*

(n=50) 800 mcg**

(n=163)

RR 95% CI Any fever 31 (62.0) 101 (62.0) 1.00 (0.78-1.28)

Mild/tolerable 9 (29.0) 40 (39.6) 0.73 (0.40-1.34) Moderate/neutral 18 (58.1) 16 (15.8) 3.67 (2.14-6.29) Severe/intolerable 4 (12.9) 44 (43.6) 0.30 (0.12-0.76) Don’t know 0 (0.0 1 (1.0) --

Any shivering 38 (76.0) 110 (67.5) 1.13 (0.93-1.36) Mild/tolerable 11 (28.9) 42 (38.2) 0.76 (0.44-1.32) Moderate/neutral 22 (57.9) 12 (10.9) 5.31 (2.92-9.66) Severe/intolerable 5 (13.2) 55 (50.0) 0.26 (0.11-0.61) Don’t know 0 (0.0) 1 (0.9) --

Women’s acceptability of overall side effects

Acceptable Neutral Not acceptable Don’t know

40 (80.0) 7 (14.0) 3 (6.0) 0 (0.0)

N/A

N/A

^Rates of side effects were compared between two separate studies testing two different regimens of misoprostol for treatment of PPH among Ecuadorian women with PPH enrolled at a maternity hospital in Quito, Ecuador. *This study enrolled Ecuadorian women exposed to uterotonics prophylactically and treated with 600 mcg sublingual misoprostol for PPH (León et al, 2012) ** These data are taken from another study that enrolled Ecuadorian women who were not exposed to uterotonics prophylactically and treated with 800 mcg sublingual misoprostol. (These data were collected as part of a multi-country RCT (Winikoff et al 2010, country-level data not shown in publication).

11.2 Misoprostol and breastfeeding

Misoprostol enters human milk if given to a nursing mother. Newborns of the mothers that take misoprostol could potentially develop the drug’s side effects. However, the maximum concentration in the breast milk (21 pg/mL peaks at 1 hour, followed by a rapid decline in levels) is much lower than ergometrine. Furthermore, after 5 hours of a single oral dose of 600 mcg of misoprostol, the levels in breast milk is unmeasurable. Vogel et al. (2004) estimated that for a nursing volume of 30 mL, the maximum amount of misoprostol delivered in the breast milk is 109 pg, representing approximately 3 X 10-5 mg/kg in a 3.5kg newborn (1/100 that in the mother). Because the levels of misoprostol in breast milk are so small and decline very rapidly, the risk to the infant is minimal with a single dose. In a study by Derman et al. administering misoprostol as PPH prevention to women after delivery, there were no differences in reports of fever, vomiting or diarrhea between newborns exposed to misoprostol versus placebo (Derman et al 2006). Misoprostol is contraindicated for nursing mothers when used to treat or prevent gastric

of 37

ulcers1. When administered for postpartum hemorrhage prevention, misoprostol has no breastfeeding contraindications (Alfirevic et al 2007); FIGO recommends that after the birth and before delivery of the placenta, breastfeeding should be encouraged (FIGO 2012).

11.3 Misoprostol and maternal mortality

Postpartum hemorrhage is one of the major contributors to maternal mortality, and no studies have been large enough to adequately assess whether or not the possibility of PPH treatment with misoprostol (or any uterotonics) will impact maternal mortality rates. However, several studies suggest that misoprostol may play a role in saving lives given that it could be used at all levels of the health care system (Sutherland et al 2009; Pagel et al 2009). Efforts have been made to uncover whether there is an association between misoprostol use for prevention and treatment of post-partum hemorrhage and subsequent maternal death. A review by Hofmeyr and Gülmezoglu (2008) found eleven deaths among more than 40,000 women in forty-seven trials on misoprostol for PPH. Of these 11 deaths, 8 of the women were given misoprostol [RR 2.0, 95% CI 0.68 - 5.83]. Meta-analysis of the seven randomized controlled trials testing misoprostol for treatment of postpartum hemorrhage found a non-significant association between misoprostol and maternal mortality: 6/1857 misoprostol vs. 1/1870 control, RR (95%CI) 6.04 (0.73-50.14), p=0.07). In six of these seven trials, all patients were also given oxytocin during the third stage of labor and/or for treatment of PPH. Only one trial tested misoprostol alone for PPH treatment in women not exposed to oxytocin and in that trial there were no deaths among the 488 women given misoprostol.

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group

12.1 Range of Costs for the Proposed Medicine

The International Drug Price Indicator Guide 2011 published by Management Sciences for Health (MSH), was used to obtain present prices of misoprostol. The median supplier price listed was USD 0.3939 per 200μg tablet of misoprostol (USD 1.58 per dose for treatment). The median price paid by the three buyers listed was USD 0.09 per tablet (range USD 0.0564-0.17); or USD 0.36 per dose for PPH treatment. Table 17 shows supplier price in USD and Table 18 shows buyer costs as listed in the report. A survey on the annual sales and manufacturer prices for 200-ug misoprostol found 85 registered products available worldwide. Based on this analysis and market trends, the authors concluded that misoprostol access is improving in low-income regions where it could have a significant impact on maternal mortality and morbidity (Fernandez MM et al, 2009). In May 2010, misoprostol became eligible for the WHO’s Prequalification of Medicines Programme; efforts are now underway to support applications from generic manufacturers of misoprostol. As misoprostol products achieve pre-qualification in the future, product availability may increase, and the unit price could drop making the drug even more cost effective.

1 The standard dose for treatment of gastric ulcers dose is 600 mcg (3 tablets), 3 times a day, for 2-3 weeks, depending on need.

of 37

Table 16. Supplier price information (in US$) Source Package Package Price Unit Price MEDEOR/TZ 28 Tab-cap (Tablets) $16.37 0.5846/tab-cap MEDS 30 Tab-cap $ 6.10 0.2032/tab-cap

Median Unit Price Lowest Unit Price Highest Unit Price High/Low Ratio

0.3939/tab-cap 0.2032/tab-cap 2.88 Highest Price 0.5846/tab-cap Table 17. Buyer Prices (USD) for 200 μg misoprostol tablets Buyer Package

Price (100 tablets)

Unit Price (USD)

Price per Dose (4 Tablets; 800μg)*

Organization of Eastern Caribbean States Pharmaceutical Procurement Service (OECS/PPS) 100 Tab-cap (Tablets)

9.00 .0900 .36

BDS 100 Tab-cap (Tablets) $ 17.86 0.1786 .7144 Camerwa 100 Tab-cap (Tablets) $5.64 .0564 .2256

Median Unit Price Lowest Unit Price

Highest Unit Price

High/Low Ratio

0.0900 0.0564 3.17 0.1786

12.2 Comparative Cost-Effectiveness

When evaluating cost-effectiveness, it is important to look at the total cost of the treatment, which includes the unit cost of the medicine and any associated costs required to administer the drug safely and effectively. When compared to misoprostol, oxytocin has higher administration costs because it requires needles, syringes and tools to ensure safe injection, disposal and infection prevention practices. Unlike misoprostol, which can be stored at room temperature, oxytocin requires protection from light and temperature-controlled storage to prevent loss of potency, which may add to the overall cost burden. Ergometrine has similar administration and storage costs. Such requirements make oxytocin and ergometrine inaccessible/unavailable in rural/remote settings, leaving misoprostol as the only intervention that can be offered in these places. In such circumstances, it is irrelevant whether misoprostol is less economically efficient as it is the only treatment option available. When this is the case, utilizing misoprostol to treat to treat PPH may be more cost-effective than referral to higher level care with its associated costs. Side effects from misoprostol include high temperature and shivering but these are transient, and rarely require additional medical treatments. Therefore, the costs to treat side effects are estimated to be minimal. One study examined the cost-effectiveness of misoprostol for PPH treatment and its comparative cost-effectiveness to other treatment methods (Seligman and Xingzhu 2006). In this study, the authors assessed the net costs, cost-effectiveness, cost-benefit ratios and net benefits for preventative and curative interventions for PPH in four countries (Argentina, Bangladesh, India,

of 37

and Nepal). In their analysis, the authors show that, at present, there is considerable variation in the cost per Disability-Adjusted Life Year (DALY) averted due to the diversity of drug prices, labor and delivery patterns, and assumed coverage of each intervention in the four study countries.

13. Comparative Cost-Effectiveness – Summary All of the interventions seeking to address PPH have a positive return. For now, misoprostol is perhaps the easiest uterotonics to offer in most rural settings where provision of oxytocin intravenously continues to pose a challenge. As more uterotonics enter the market, the cost of the full package of interventions for PPH care is likely to drop.

14. Summary of regulatory status of the medicine

Many formulations of misoprostol are available (See Appendix 1). Misoprostol was originally approved in the United States, where it was marketed and distributed as Cytotec® by Searle (now Pfizer). More than a dozen countries are now planning to or are in the midst of introducing misoprostol for PPH treatment and several pharmaceutical companies are pursuing dedicated PPH products.

15. Availability of pharmacopoeial standards Misoprostol (standards available in BAN, USAN, rINN) U.S. Pharmacopeia conducted a review and made the following conclusion: “Upon review of the studies included in the attached evidence tables on misoprostol, the consensus of the U.S. Pharmacopeia Expert Advisory Panel is that prevention of postpartum hemorrhage should be considered as an Accepted indication in the USP Drug Information (DI) monograph on misoprostol. They recommended misoprostol as an alternative agent in reducing the incidence of postpartum hemorrhage, especially in situations in which oxytocin and other uterotonic drugs are not available” (US Pharmacopeia 2001).

16. Proposed text for the WHO model formulary

SECTION: 22.01.00.00 Oxytocics FORMULATION (dosage form and strength): Oral tablet: 200 micrograms; ATC Code: A02BB01; Type of List: Core List.

DISEASE/INDICATION: Treatment of postpartum hemorrhage.

RATIONALE FOR INCLUSION: Misoprostol offers a low-cost, easy to administer means to treat postpartum hemorrhage, one of the major contributors to maternal morbidity and mortality worldwide.

of 37

GENERAL INFORMATION: Misoprostol is a complementary drug for medical termination of pregnancy of up to 63 days gestation where this is permitted under national law, for management of incomplete abortion/miscarriage in women with uterine size ≤ 12 weeks gestational age and for induction of labour. The drug is also used for prevention of postpartum hemorrhage in many jurisdictions.

USES: Treatment of postpartum hemorrhage (used alone). CONTRAINDICATIONS (for use in PPH treatment): None. DOSE: Treatment of postpartum hemorrhage, sublingual administration (under the tongue), ADULT and ADOLESCENT a single dose of 800 micrograms. NOTE: None ADMINISTRATION: For treatment of postpartum hemorrhage, sublingual administration of four 200-microgram tablets (800 micrograms total) is recommended. ADVERSE EFFECTS: shivering, fever.

17. References Abdel-aleem H, El-Nashar I, Abdel-Aleem A. Management of severe postpartum hemorrhage with misoprostol. Int J Gynecol Obstet 2001, 72:75-76. AbouZahr C. Global burden of maternal death and disability. Br Med Bull 2003;67(1):1-11. AbouZahr C, Wardlaw T. Maternal mortality at the end of a decade: signs of progress? Bulletin of the World Health Organization 2001;79:561-568. ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists Number 76, October 2006: postpartum haemorrhage. Obstet Gynecol. 2006 Oct;108(4):1039-47. Adekanmi OA, Purmessur S, Edwards G, Barrington JW. Intrauterine misoprostol for the treatment of severe recurrent atonic secondary postpartum haemorrhage. BJOG 2001, 108:541-545. ACOG Practice Bulletin No. 76. Postpartum hemorrhage. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006;108:1039–47. Alfirevic Z, Blum J, Walraven G, Weeks A, Winikoff B. Prevention of postpartum hemorrhage with misoprostol. International Journal of Gynecology and Obstetrics 2007;99(Supplement 2): S198-S201. Amant F, Spitz B, Timmerman D, Corremans A, Van Assche FA, Misoprostol compared with methylergometrine for the prevention of postpartum hemorrhage: a double-blinded randomized trial. British Journal Obstetrics Gynaecology. 1999; 106(10): 1066 – 70.

of 37

Barauh M, Cohn G. Efficacy of misoprostol as second-line therapy for the treatment of primary postpartum hemorrhage. J Reprod Med. 2008 Mar;53(3):203-6. Baskett TF, Persad VL, Clough HJ, Young DC. Misoprostol versus oxytocin for the reduction of postpartum blood loss. Int J Gynaecol Obstet. 2007 Apr;97(1):2-5. Blum J, Alfirevic Z, Walraven G, Weeks A, Winikoff B. Treatment of postpartum hemorrhage with misoprostol. Int J Gynaecol Obstet 2007, Suppl 2:202-205. Blum, Jennifer, et al. "Treatment of post-partum haemorrhage with sublingual misoprostol verses oxytocin in women receiving prophylactic oxytocin: a double-blind, randmoised, non-inferiorrity trial." The Lancet 375 (2010): 217-23. Bhullar A, Carlan S, Hamm J, Lambery N, White L, Richichi K. Buccal misoprostol to decrease blood loss after vaginal delivery: a randomized trial. Obstetrics and Gynaecology 2004;104:1282-1288. Boletin de la Direccion Ejecutiva y Comites de La Federacion Latinoamericana de Sociedades de Obstetricia y Ginecologia (FLASOG). Consenso Latinoamericano sobre usos del Misoprostol en Obstetricia y Ginecologia. Articulo Central, Volumen 1, Numero 1, Mayo 2012: 4-7. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol. 2008 Dec;22(6):999-1012. Epub 2008 Sep 25. Review. Chandhiok N, Dhillon B, Datey S, Mathur A, Saxena N. Oral misoprostol for prevention of postpartum hemorrhage by paramedical workers in India. International Journal of Gynecology & Obstetrics 2006;92(2):170-175. Chong YS, Chua S, Arulkumaran S. (1997). Letter to the Editor: Severe hyperthermia following oral misoprostol in the immediate postpartum period. Obstetrics & Gynecology, 90(4) 703-704. Chong YS, Chua S, Shen L, Arulkumaran S. (2004). Does the route of administration of misoprostol make a difference? The uterotonic effect and side effects of misoprostol given by different routes after vaginal delivery. Obstetrics & Gynecology, 131, 191-198. de Bernis L, Sherratt DR, AbouZahr C, Van Lerberghe W. Skilled attendants for pregnancy, childbirth and postnatal care. Br Med Bull 2003;67(1):39-57. Derman RJ, Kodkany BS, Goudar SS, Geller SE, Naik VA, Bellad MB, Patted SS, Patel A, Edlavitch SA, Hartwell T, Chakraborty H, Moss N: Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial. Lancet 2006, 368:1248-1253.

http://www.ncbi.nlm.nih.gov/pubmed/18819848


of 37

Donnay F. Maternal survival in developing countries: what has been done, what can be achieved in the next decade. International Journal of Gynecology & Obstetrics 2000;70(1):89-97. Durocher, J, J Bynum, W Leon, G Barrera, and B Winikoff. "High fever following postpartum administration of sublingual misoprostol." British Journal of Obstetrics and Gynecology, 2010. BJOG 2010;117:845-52. El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Use of oral misoprostol in the prevention of postpartum haemorrhage. BJOG 1997; 104: 336-39. Enakpene C et al. Oral misoprostol for the prevention of primary post-partum hemorrhage during third stage of labor. J Obstet Gynaecol Res 2007, 33(6): 810–817. Fernandez MM, Coeytaux F, Ponce de León RG, Harrison DL. Assessing the global availability of misoprostol. International Journal of Gynecology and Obstetrics 105 (2009) 180–186. Geller SE, Goudar SS, Adams MG, Naik VA, Patel A, Bellad MB, Patted SS, Edlavitch SA, Moss N, Kodkany BS, Derman RJ. Factors associated with acute postpartum hemorrhage in low-risk women delivering in rural India. International Journal of Gynecology & Obstetrics 2008;101(1):94-99. Graham WJ, Fitzmaurice AE, Bell JS, Cairns JA. The familial technique for linking maternal death with poverty. Lancet 2004;263:23-27. Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al. WHO multicentre randomised study of misoprostol in the management of the third stage of labour. Lancet 2001;358(9283): 689-695. Gülmezoglu AM, Forna F, Villar J, Hofmeyr G. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000494. Hagan MC, Foreman KJ, Naghavi M, Ahn SY, Wang M, Makela SM, Lopez AD, Rafael L, Murray CJL. Maternal mortality for 181 countries, 1980-2008: a systematic analysis of progress towards Millennium Development Goal 5. The Lancet 2010; 375; 1609-23. Hartwell T. Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial. The Lancet 2006;368(9543):1248. Hofmeyr JG, Nikodem VC, de Jager M, Gelbart BR. A randomized placebo controlled study of oral misoprostol in the third stage of labour. Br J Obstet Gynaecol 1998;105: 971-975. Hofmeyr JG, Gülmezoglu AM. Misoprostol for the prevention and treatment of postpartum haemorrhage. Best Practice & Research Clinical Obstetrics and Gynacology (2008), doi:10.1016/j.bpobgyn.2008.08.005.

of 37

Hofmeyr JG, Ferreira S, Nikodem VC, Mangesi L, Singata M, Jafta Z, et al. Misoprostol for treating postpartum hemorrhage: a randomized controlled trial. NJOG 2004;111(9):1014-9. Hofmeyr GJ, Walraven G, Gülmezoglu AM, Alfirevic Z, Villar J. Misoprostol to treat postpartum hemorrhage: a systematic review. BJOG 2005, 112:547-553. Høj L, Cardoso P, Nielsen BB, Hvidman L, Nielsen J, Aaby P. Effect of sublingual misoprostol on severe postpartum hemorrhage in a primary health centre in Guinea-Bissau: randomized double blind clinical trial. BMJ 2005;331(7519): 723. Hogerzeil H and Walker G. Instability of (methyl)ergometrine in tropical climates: an overview. European Journal of Obstetrics & Gynecology 1996;69: 25 – 29. International Federation of Gynecology and Obstetrics (FIGO). Treatment of postpartum hemorrhage with misoprostol - FIGO GUIDELINES. Int J Gynecol Obstet 2012;119(3). International Federation of Gynecology and Obstetrics (FIGO) Prevention and treatment of postpartum hemorrhage in low-resource settings offer a comprehensive overview of a combination of best practice approaches and life-saving interventions along a continuum of care from community to hospital. Int J Gynecol Obstet 2012; 117(2): 108–118. International Confederation of Midwives (ICM), International Federation of Gynecology and Obstetrics (FIGO). Prevention and Treatment of Post-partum Haemorrhage: New Advances for Low Resource Settings Joint Statement. The Hague: ICM; London: FIGO, 2006. Khan KS, Wojdyla D, Say L, Gu lmezoglu AM, Van Look P. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367:1066-1074. Lalonde A, Daviss B, Acista A, Herschderfer K. Postpartum hemorrhage today: ICM/FIGO initiative 2004-2006. International Journal of Gynecology & Obstetrics 2006;94:243-253. León W, Durocher J, Barrera G, Pinto E, Winikoff B. Dose and side effects of sublingual misoprostol for treatment of postpartum hemorrhage: what difference do they make? BMC Pregnancy Childbirth. 2012 Jul 7;12:65. doi: 10.1186/1471-2393-12-65. Lokugamage AU, Sullivan KR, Niculescu I, Tigere P, Onyangunga F, El Refaey H, Moodley J, Rodeck CH. A randomized study comparing rectally administered misoprostol versus Syntometrine combined with an oxytocin infusion for the cessation of primary post partum hemorrhage. Acta Obstet Gynecol Scand 2001, 80:835-839. Lubaki J-P, Musiti Ngolo J-R, Zikudieka Maniati L. Active management of third stage of labour, post–partum haemorrhage and maternal death rate in the Vanga Health Zone, Province of Bandundu, Democratic Republic of the Congo. Afr J Prm Health Care Fam Med. 2010;2(1), Art. #76, 3 pages. DOI: 10.4102/phcfm.v2i1.76

of 37

Maine D. Safe motherhood programs: options and issues. New York: Columbia University; 1993 (42). MSH. International Drug Price Indicator Guide. 2011 Edition. Cambridge, MA: Management Sciences for Health. Accessed 11/16/2012 at: http://erc.msh.org/dmpguide/resultsdetail.cfm?language=english&code=MIS200T&str=200 mcg&desc=Misoprostol&pack=new&frm=TAB-CAP&rte=PO&class_code2=22.1.&supplement=&s_year=2011&year=2011&word= McCormick ML, Sanghvi HCG, Kinzie V, McIntosh N. Preventing postpartum hemorrhage in low-resource settings. International Journal of Gynecology & Obstetrics 2002;77(267-275). Mousa H, Alfirevic Z. Treatment for primary postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;2007(1):1-25.

Mousa HA, Cording V, Alfirevic Z. Risk factors and interventions associated with major primary postpartum hemorrhage unresponsive to first-line conventional therapy. Acta Obstet Gynecol Scand. 2008;87(6):652-61.

Mousa H, Walkinshaw S. Major postpartum haemorrhage. Current Opinion in Obstetrics and Gynecology 2001;13:595-603 Ng PS, Chan AS, Sin WK, Tang LC, Cheung KB, Yuen PM. A multicentre randomized controlled trial of oral misoprostol and i.m. syntometrine in the management of the third stage of labor. Human Reproduction 2001; 16: 31-35. Ng PS, Lai CY, Sahota DS, Yuen PM. A double-blind randomized controlled trial of oral misoprostol and intramuscular syntometrine in the management of the third stage of labor. Gynecol Obstet Invest. 2007;63(1):55-60. Oboro VO, Tabowei TO. A randomised controlled trial of misoprostol versus oxytocin in the active management of the third stage of labour. Journal of Obstetrics and Gynaecology 2003;23(1):13-16. Oboro VO, Tabowei TO, Bosah JO. Intrauterine misoprostol for refractory postpartum hemorrhage. Int J Gynecol Obstet 2003, 80:67-68. O'Brien P, El-Refaey H, Gordon A, Geary M, Rodeck CH. Rectally administered misoprostol for the treatment of postpartum hemorrhage unresponsive to oxytocin and ergometrine: a descriptive study. Obstet Gynecol. 1998 Aug;92(2):212-4. Ozan H, Bilgin T, Ozsarac N, Ozerkan RK, Cengiz C. Misoprostol in uterine atony: a report of 2 cases. Clin Exp Obstet Gynecol 2000, 27:221-222. Pagel C, Lewycka S, Colbourn T, Mwansambo C, Meguid T, Chiudzu G, Utley M, Costello AM.

http://www.ncbi.nlm.nih.gov.ezproxy.cul.columbia.edu/pubmed/18568465

http://www.ncbi.nlm.nih.gov.ezproxy.cul.columbia.edu/pubmed/18568465

of 37

Estimation of potential effects of improved community-based drug provision, to augment health-facility strengthening, on maternal mortality due to post-partum haemorrhage and sepsis in sub-Saharan Africa: an equity-effectiveness model. Lancet. 2009 Oct 24;374(9699):1441-8. Epub 2009 Sep 23. Erratum in: Lancet. 2009 Oct 24;374(9699):1422 Potts M, Hemmerling A. The worldwide burden of postpartum haemorrhage: Policy development where inaction is lethal. International Journal of Gynecology & Obstetrics 2006;94(Supplement 2):S116. Prata N, Mbaruku G, Campbell M, Potts M, Vahidnia F: Controlling postpartum hemorrhage after home births in Tanzania. Int J Gynaecol Obstet 2005, 90:51-55. Prata N, Montagu D, Jefferys E. Private sector, human resources and health franchising in Africa. Bulletin of the World Health Organization 2005;83:274-279. Prata N, Hamza S, Gypson R, Nada K, Vahidnia F, Potts M. Misoprostol and active management of the third stage of labor. International Journal of Gynecology & Obstetrics 2006;94(2):149-155. Prata N, Sreenivasa A, Vahidniaa F, Potts M. Saving maternal lives in resource-poor settings: Facing reality. Health Policy 2008;doi:10.1016/j.healthpol.2008.05.007 Prendiville WJ, Harding JE, Elbourne DR, Stirrat GM. The Bristol third stage trial: active versus physiological management of third stage of labour. BMJ 1988;297: 1295-1300. Prequalification of Medicines Programme. A United Nations Programme managed by WHO. http://apps.who.int/prequal/info_general/documents/FAQ/FAQ_RH-medicines_V3.pdf Accessed November 19, 2012. Royal College of Obstetricians and Gynaecologists. RCOG Green-top Guideline No. 52. May 2009 Seligman B and Xingzhu, L. Policy and Financing Analysis of Selected Postpartum Hemorrhage Interventions: Country Summary. Abt Associates, Inc. 2006. Sheldon W, Blum J, Durocher J, Winikoff B. Misoprostol for the Prevention and Treatment of Postpartum Hemorrhage. Expert Opin. Investig. Drugs, 2012;21(2):235-50. Sibley L, Sipe TA. What can a meta-analysis tell us about traditional birth attendant training and pregnancy outcomes? Midwifery 2004;20:51-60. Shojai R, Debriere R, Dhifallah S, Courbiere B, Ortega D, d’Ercole C, Boubli L. [Rectal misoprostol for postpartum hemorrhage.] Gynecol Obstet Fertil 2004, 32:703-707.




of 37

Shojai R, Piechon L, d’Ercole C, Boubli L, Ponties JE. [Rectal administration of misoprostol for delivery induced hemorrhage. Preliminary study.] J Gynecol Obstet Reprod Biol 2001, 30:572-575. Sosa CG, Althabe F, Belizan JM, Buekens. Use of oxytocin during early stages of labor and its effect on active management of third stage of labor. Am J Obstet Gynecol 2011;204(3):238.e1-5. Stanton C, Koski A, Cofie P, Mirzabagi E, Grady BL, Brooke S. Uterotonic drug quality: an assessment of the potency of injectable uterotonic drugs purchased by simulated clients in three districts in Ghana. BMJ Open. 2012 May 3;2(3). pii: e000431. doi: 10.1136/bmjopen-2011-000431. Print 2012. Surbek DV, Fehr PM, Hosli I, Holzgreve W. Oral misoprostol for third stage of labor: A randomized-placebo controlled trial. Obstetrics & Gynecology 1999; 94: 255-58. Sutherland T Bishai D. Cost-effectiveness of misoprostol and prenatal iron supplementation as maternal mortality interventions in home births in rural India. International Journal of Gynecology and Obstetrics 104 (2009) 189–193. Sutherland T, Meyer C, Bishai D, Geller S, Miller S, Community-based distribution of misoprostol for treatment or prevention of postpartum hemorrhage: Cost-effectiveness, mortality, and morbidity reduction analysis, Int J Gynecol Obstet 2010 Mar;108(3):289-94. Epub 2010 Jan 15. Tang OS, Schweer H, Seyberth HW et al. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002; 17: 332-336. Tsu VD, Shane B. New and underutilized technologies to reduce maternal mortality: call to action from a Bellagio workshop. International Journal of Gynecology & Obstetrics 2004;85(Supplement 1):S83-S93. Tunçalp Ö, Hofmeyr GJ, Gülmezoglu AM. Prostaglandins for preventing postpartum haemorrhage.Cochrane Database Syst Rev. 2012 Aug 15;8:CD000494. United States Pharmacopeia Misoprostol for Prevention of Postpartum Hemorrhage: An Evidence-based Review (2001), http://www.usp.org/pdf/EN/dqi/misoprostolReport.pdf UN. The Millennium Development Goals Report. New York: United Nations, 2007. UN. The Millennium Development Goals Report. New York: United Nations, 2010. UNPF. Maternal mortality update 2002, a focus on emergency obstetric care. New York: United Nations Population Fund, 2003.

http://www.usp.org/pdf/EN/dqi/misoprostolReport.pdf

of 37

Villar J, Gulmezoglu AM, Hofmeyr GJ, Forna F. Systematic review of randomized controlled trials of misoprostol to prevent postpartum hemorrhage. Obstetrics and Gynaecology 2002;100(6):1301-1312. Vogel D, Burkhardt T, Rentsch K, Schweer H, Watzer B, Zimmermann R, von Mandach U. Misoprostol versus methylergometrine: Pharmacokinetics in human milk. American Journal of Obstetrics and Gynecology 2004;191(6):2168-2173. Walraven G, Blum J, Dampha Y, Sowe M, Morison L, Winikoff B, Sloan N. Misoprostol in the management of the third stage of labour in the home delivery setting in rural Gambia: a randomised controlled trial. British Journal of Obstetrics and Gynaecology 2005;112(9):1277. Walraven G, Dampha Y, Bittaye B, Sowe M, Hofmeyr J. Misoprostol in the treatment of postpartum haemorrhage in addition to routine management: a placebo randomized controlled trial. BJOG 2004, 111:1014-1017. Wannmacher L. “Safety Profile of Misoprostol for Obstetrical Indications”. Word Health Organization 2010. WHO. Mother-baby package: implementing safe motherhood in countries; practical guide. Geneva. 1994. WHO. Maternal Mortality in 2005: Estimates developed by WHO, UNICEF, UNFPA, and the World Bank. Geneva: The World Health Organization, 2005. WHO. Proportion of births attended by a skilled attendant - 2007 Updates. Department of Reproductive Health and Research. Geneva: World Health Organization, 2007. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization, 2012. Widmer M, Blum J, Hofmeyr GJ, Carroli G, Abdel-Aleem H, Lumbiganon P, Ngoc NTN,Wojdyla D, Thinkhamrop J, Singata M, Mignini LE, Abdel-Aleem MA, Thach TS, Winikoff B. Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial. The Lancet 2010; 375: 1808–13. Winikoff, Beverly, et al. "Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind randmoised non-inferiority trial." The Lancet. Published online Jan 7. DOI:10.1016/S0140-6736(09)61924-3. Zachariah E, Naidu M, Seshadri L. Oral misoprostol in the third stage of labor. International Journal of Gynecology & Obstetrics 2006;92(1):23-26. Zieman M, Fong SK, Benowitz NL et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997: 90; 88-91.

of 37

Zuberi N, Durocher J, Sikander R, Baber N, Blum J, Walraven G. Misoprostol in addition to routine treatment of postpartum hemorrhage: A hospital-based randomized controlled-trial in Karachi, Pakistan. BMC Pregnancy and Childbirth. BMC Pregnancy Childbirth. 2008 Aug 21;8:40.

18. Appendix A – Partial List of Misoprostol Trade Names Product name Form Composition Company Alsoben Tab Misoprostol 200mcg Unimed Pharm, Korea Asotec Tab Misoprostol 200mcg Square, Bangladesh Cirotec Tab 200mcg Yoo Young, South Korea Cyrux Tab 200mcg Serral, Mexico Cystol Tab 200mcg Korea United Pharm, South Korea Cytil Tab 200mcg Tecnoquimicas, Colombia Cytil Tab Misoprostol 200mcg Tecnoquímicas, Colombia Cytofine Tab 200mcg Master Farma, Peru Cytolog Tab Misoprostol 200mcg Zydus Cadila, India Cytomis Tab Misoprostol 200mcg Incepta Pharma, Bangladesh Cytotec Tab 200mcg Kaken Seiyaku, Japan Cytotec Tab 200mcg Pfizer Cytotec Tab 200mcg Aliraif Searle, Turkey Cytotec Tab Misoprostol 100mcg IVAX, US Cytotec Tab Misoprostol 200mcg IVAX, US Cytotec Tab Misoprostol 200mcg Pfizer, USA Gastec Tab 200mcg Samchully Ph-Chung Gei, South Korea Gastotec Tab 200mcg JRP, South Korea Gastrul Tab 200mcg Gastrul, Indonesia Gastrul Tab Misoprostol 200mcg Farenheit, Indonesia Gistol Tab 200mcg Withusmedipharm, South Korea GMisoprostol Tab Gonoshasthaya Parmaceuticals, Dhaka,

Bangladesh Gymiso Tab Misoprostol 200mcg HRA Pharma, France Isovent Tab Square Pharmaceuticals, Dhaka,

Bangladesh Kontrac Tab 200mcg Fourts India, India Medabon Tab * contains 1 tab mife 200mg and 4

tabs of miso 200mcg Sun Pharma, Mumbai, India

Mesopil Tab Misoprostol 200mcg Nicholas Piramal, India Mesowis Tab Misoprostol 200mcg Wisdom, INDIA Mirolut Tab Misoprostol 200mcg MIR Pharma, Russia Misel Tab 200mcg Shin Poong, South Korea Misive/Bial Tab Madrid, Spain Miso Tab 200mcg Bestochem, India

of 37

Miso tab Tab Misoprostol 200mcg Bestochem, India Misogent Tab 200mcg Aristo Pharma, India Misogon Tab 200mcg German Remedies, India Misoplus Tab 200mcg Walse Korea, South Korea Misoprolen Tab 200mcg Intipharm, Peru Misoprost Tab Misoprostol 100mcg Cipla, India Misoprost Tab Misoprostol 200mcg Cipla, India Misoprostol Tab 200mcg Sh.Huan Lian Pharma, China Misoprostol Tab 200mcg BJ.Pharm.FTY No.3, China Misoprostol Tab 200mcg Servimedic, Uruguay Misoprostol Tab Misoprostol 200mcg Indofarma, Indonesia Misoprostol Tab Misoprostol 200mcg Pentcroft Pharma, Russia Misoprostol NLS

Tab 200mcg Nelson Korea Pharma, South Korea

Misostad Tab Misoprostol 200mcg Stada, Vietnam Misotac Tab Misoprostol 200mcg Sigma Pharm, Egypt Misotol Tab Misoprostol 200mcg Resmed, India Misotrax Tab 200mcg Genetica, India Misotrol Tab 200mcg Sanofi Aventis, Chile Mizolast Tab 200mcg FDC, India Mizoprostol Tab Beijing Zizhu Pharmaceutical Co,

China Noprostol Tab 200mcg Novell Pharm, Indonesia Prestakind Tab Misoprostol 200mcg Mankind, India Prostokos Tab Misoprostol 200mcg Hebron Pharma, Brazil Sintec Tab 200mcg Sam Chum Dang, South Korea ST Mom Tab 200mcg Zafa Pharmaceutical Laboratories

(PVT) Ltd Misoclear Tab 200mcg Zafa Pharmaceutical Laboratories

(PVT) Ltd Tector Tab Misoprostol 200mcg Zee Lab, India U-Miso Tab Misoprostol 200mcg U-Liang, Taiwan Vagiprost Tab Adwia, el Oubor, Egypt Zitotec Tab Misoprostol 100mcg Sun Pharma, India Zitotec Tab Misoprostol 200mcg Sun Pharma, India

Grade Tables: Management of Postpartum hemorrhage with misoprostol

TABLE 1: Adjunct use of misoprostol in women who received prophylactic oxytocin in the third stage of labour?

Author(s): Abalos E, Chou D Date: 2008-11-11 Question: Should misoprostol vs placebo be used for treatment of post partum haemorrhage? Settings: LMIC Bibliography: HA Mousa, Z Alfirevic. Treatment for primary postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD003249. DOI: 10.1002/14651858.CD003249.pub2., Widmer et al 2010; Zuberi et al 2008.

Quality assessment Summary of findings

ImportanceNo of patients Effect

Quality No of studies Design Limitations Inconsistency Indirectness Imprecision Other

considerationsprimary outcomes controls

Relative(95% CI)

Absolute

Additional blood loss = or > 500 ml 4 randomised

trial no serious limitations

no serious inconsistency

no serious indirectness

serious none 170/929 (18.3%)

200/950(21.1%)

RR 0.83 (0.64 to

1.07)

29 fewer per 1,000

⊕⊕⊕⊕ HIGH CRITICAL





very serious none 20/899 (2.2%)

27/915 (3.1%)

RR 0.76 (0.43 to

1.34)

7 fewer per 1,000

⊕⊕⊕Ο MODERATE CRITICAL

Blood transfusion 4 randomised





147/949 (14.5%)

RR 0.96 (0.77 to

1.19)

6 more per 1000


Hysterectomy 3 randomised


serious4 no serious indirectness


5/919 0.41%)

RR 0.93 (0.16 to

5.41)

0 fewer per 1,000

⊕⊕ΟΟ LOW CRITICAL

Additional uterotonics 4 randomised




serious none 253/894 (28.3%)

271/910 (28.3%)

RR 0.96 (0.84 to

11 fewer per 1,000

⊕⊕⊕⊕HIGH CRITICAL

1.1) Shivering 4 randomised




Serious1 none 556/928 (59.9%)

270/948 (17.7%)

RR 2.24 (1.72 to

2.91)

219 fewer per

1,000

⊕⊕⊕Ο MODERATE IMPORTANT

1 Wide confidence interval

TABLE 2: Misoprostol vs oxytocin for treatment of post partum haemorrhage in women receiving oxytocics in the third stage of labour?

(Metin. This is the table that was prepared for the treatment guidelines but did not appear in the final document. I have only changed the title to match the editorial changes made in the following table #3 and updated the bibliography)

Author(s): Abalos E, Chou D Date: 2008-11-11 Question: Should misoprostol vs oxytocin be used for treatment of postpartum haemorrhage in women receiving oxytocics in the third stage of labour? Settings: Bibliography: Blum et al Lancet 2010




considerations misoprostol oxytocinRelative

(95% CI)

Absolute

Additional blood loss = or > 500 ml (calibrated drops) 1 randomised




serious1 none 58/405 (14.3%)

52/399 (13%)

RR 1.09 (0.77 to

1.55)

11 more per 1,000






serious2 none 0/0 (0%) 0/0 (0%) RR 0 (0 to 0)

0 fewer per 1,000

⊕⊕⊕ΟMODERATE CRITICAL





serious3 none 22/405 (5.4%)

18/399 (4.5%)

RR 1.21 (0.66 to

2.22)

9 more per 1,000







46/399 (11.5%)

RR 0.84 (0.56 to

1.25)

18 fewer per 1,000


Temperature > 40°C 1 randomised





1/399 (0.3%)

RR 4.93 (0.58 to 41.98)

11 more per 1,000


1 Anything from a 23% reduction to a 50% increase 2 Although significant, CI is wide 3 Anything from 44% reduction to a two-fold increase 4 Anything from a 44% reduction to a 25% increase 5 Anything from a 42% reduction to a forty two-fold increase

TABLE 3: Misoprostol vs oxytocin for treatment of post partum haemorrhage in women who did not receive prophylactic oxytocin in the third stage of labour?

Author(s): Abalos E, Chou D Date: 2008-11-11 Question: Should misoprostol vs oxytocin be used for treatment of post partum haemorrhage in women NOT receiving oxytocin in the third stage of labour? Settings: LMIC Bibliography: Winikoff et al Lancet 2010




considerations misoprostol oxytocinRelative

(95% CI)

Absolute





no serious imprecision

none 52/488 (10.7%)

19/489 (4%)

RR 2.74 (1.64 to

4.56)

69 more per 1,000






very serious1 none 5/488 (1%) 3/489

(0.6%)

RR 1.67 (0.4 to 6.95)

4 more per 1,000

⊕⊕ΟΟ LOW CRITICAL






28/489 (6%)

RR 1.54 (0.97 to

2.44)

32 more per 1,000






no serious imprecision

none 59/489 (12.1%)

33/488 (7%)

RR 1.79 (1.19 to

2.69)

55 more per 1,000


Temperature > 40°C 1 randomised



serious3 serious4 strong association5 64/488

(13.1%) 0/489 (0%)

RR 129.27 (8.01 to 2883.1)

0 more per 1,000


1 From a 40% reduction to a seven-fold increase 2 From a 3% reduction to a 2 1/2 fold increase

3 Results concentrated in one setting 4 Although significant, confidence intervals are wide 5 Large effect in the intervention group

application for inclusion on who model list of essential medicines

Documents